Tetrahydropyridine derivatives

ABSTRACT

The present invention relates to tetrahydropyridine derivatives which have high affinity and specificity to σ receptors, whereby these compounds are thought to be effective for treatment of some psychoses.

This is a divisional application of Ser. No. 07/655585filed Feb. 15, 1991, now U.S. Pat. No. 5,149,817, issued Sep. 22, 1992.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel tetrahydropyridine derivatives with psychotropic activities.

2. Prior Art

Antidopamine agents such as haloperidol (U.S. Pat. No. 3,438,991) are used as an antipsychotic agent. Adverse reactions in the extrapyramidal tract such as delayed dyskinesia are caused by them during long-term therapy. Recently, safer drugs, rimcazole (JP. Pat. Publn. No. 55-64,585) and BMY 148021 (GB Patent No. 2,155, 925), which show high affinity to σ receptors but low affinity to dopamine receptors, have been developed as psychotropic drugs. On the other hand, the exsistence of a binding site of dextromethorphan (DM) in the central nervous system has been reported (J. Musacchio, M. Klein and L. J. Santiago, The Journal of Pharmacology and Therapeutics 247 (2), 424 (1988), High Affinity Dextromethorphan Binding Sites in Guinea Pig Brain; Further Characterization and Allosteric Interactions). DM, which is one of the most popular antitussives, is thought to be effective for ischemic encephalopathy (F. C. Tortella, M. Pellicano and N. G. Bowery, Trips, 10(12), 501 (1989), Dextromethophan and neuromodulation: old drug coughs up new activities). It is also thought that the property of σ receptors, which is labeled with [3H]3PPP adopted in the present invention, resembles that of the DM binding site (J. M. Musacchio, M. Klein and P. D. Cano 11, Life Sciences, 45, 1721 (1989), Dextromethorphan and Sigma Ligands: Common Sites but Diverse Effects).

SUMMARY OF THE INVENTION

This invention relates to novel tetrahydropyridine derivatives with psychotropic activities. Furthermore, these compounds have high affinity and specificity to σ receptors, whereby they are thought to be effective for some psychoses such as depression, mania, and acute and chronic schizophrenia, and cerebral ischemic disease.

DETAILED DESCRIPTION

The present invention relates to compounds of the formula: ##STR1## wherein Ar is phenyl or thienyl which may have identically or differently one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, substituted or unsubstituted phenyl, trifluoromethyl, and hydroxy; n is an integer of from 2 to 6; R is hydroxy or a group of the formula: ##STR2## wherein R¹ is hydrogen or lower alkyl; R² and R³ each is hydrogen or lower alkyl or taken together with the adjacent nitrogen atom may form a 5- or 6-membered heterocyclic group, which may be condensed with a benzene ring, where the heterocyclic group may have identically or differently 1 to 3 substituents selected from the group consisting of lower alkyl, halogen, oxo, pyrimidine, and substituted or unsubstituted phenyl; R⁴ is NH, O, or a single bond; X¹ and X² each is hydrogen, lower alkyl, halogen, or hydroxy; p and q each is an integer of 0 or 1, excluding the case here p is 0 when q is 1, or a pharmaceutically acceptable acid addition salt thereof.

In this specification, the term "lower alkyl" refers to a straight or branched chain C₁ to C₆ alkyl including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 2-methylbutyl, n-hexyl, isohexyl and the like.

The term "lower alkoxy" refers to C₁ to C₆ alkoxy including methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.

The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

"Substituted phenyl" means phenyl substituted by one or more substituents, of which examples are hydroxy, lower alkyl, lower alkoxy, and halogen.

The "5- or 6-membered heterocyclic group" may contain one or more additional heteroatoms including oxygen, sulfur, and nitrogen atoms, and examples of the 5- or 6-membered heterocyclic group are isothiazole, pyrozole, pyridine, pyrimidine, imidazole, and isoxazole, preferably, pyrrolidine, piperidine, piperazine, imidazolidine, thiomorpholine, morpholine, pyrazolidine, and the like. The above mentioned heterocyclic group may be condensed with a benzene ring at any position. Further they may have identically or differently 1 to 3 substituents selected from the group consisting of lower alkyl, halogen, oxo, pyrimidine, and substituted or unsubstituted phenyl.

Pharmaceutically acceptable acid addition salts include mineral acid salts such as hydrocloride, sulfate, nitrate, and phosphate, and organic acid salt such as acetate, fumarate, citrate, tartarate, maleate, and oxalate, most preferably hydrochloride, maleate and oxalate.

The compounds of this invention can be prepared by the following method. ##STR3##

METHOD A Step 1

The compound (II) is reacted with the compound of the formula:

    R(CH.sub.2)nY                                              (VI)

wherein R, Y, and n each has the same meaning as defined above in an appropriate organic solvent, if necessary in the presence of base to prepare the compound (III).

The reaction is performed at a temperature of from 50° to 200° C., preferably from 85° to 120° C., for 1-15 hours, especially for 5-10 hours.

Organic solvents which may be used are alcohols such as methanol and ethanol, ethers such as diethylether and tetrahydrofuran, dimethylformamide, acetonitrile and the like, most preferably dimethylformamide.

As the base, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, pyridine, triethylamine, and the like may be used.

Step 2

The compound (III) is subjected to dehydration in an organic solvent in the presence of the acid to prepare the compound (I a).

The reaction is performed at a temperature of from 0° to 120° C., preferably at room temperature for 1-96 hours, especially for 3-72 hours.

The same organic solvent as mentioned in Step 1 may be used.

The acid includes hydrochloride, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid.

METHOD B Step 1

The compound (II) is reacted with the compound of the formula:

    Z.sup.1 (CH.sub.2)nY                                       (VII)

wherein Z¹ Y and n each has the same meaning as defined above in an organic solvent in the presence of a base to prepare the compound (IV).

The reaction is performed at 10°-150° C., preferably from room temperature to 110° C., for 1-20 hours, especially for 3-7 hours.

The same organic solvent and the base as mentioned Method A (step 1) may be used.

The compound (VII) means phthalimide butylbromide, 3-bromo-1-chloropropane and the like.

Step 2

The compound (IV) is reacted with the compound of the formula:

    RH                                                         (VIII)

wherein R has the same meaning as defined above in an organic solvent, if necessary in the presence of base to prepare the compound (III).

The reaction is performed at 80°-200° C., preferably at 100°-130° C., for 1-24 hours, especially for 2-7 hours.

The same organic solvent and the base as mentioned Step 1 may be used.

Step 3

The compound (III) is subjected to dehydration in the same manner as Method A (step 2) to prepare the compound (Ia). Each condition is the same as Method A (step 2).

METHOD C Step 1

The compound (II) is reacted with the compound of the formula:

    HO(CH.sub.2)nY                                             (IX)

wherein Y and n each has the same meaning as defined above, preferably in the presence of the base to prepare the compound (IV).

The reaction is performed at 50°-200° C., preferably at 120°-150° C., for 3-20 hours, especially for 5-9 hours.

Step 2

The compound (IV) is reacted with a chloride of a nonmetal element to prepare the compound (V).

The reaction is performed at 0°-100° C., preferably at room temperature, for 1-48 hours, especially for 2-24 hours.

The chloride includes sulfur chloride, thionylchloride, hydrochloride, carbon tetrachloride, and the like.

Step 3

The compound (V) is reacted with RH (VIII) to prepare the compound (III).

The reaction is performed at 0°-100° C., preferably from room temperature to 50° C. for 1-96 hours, preferably for 3-72 hours.

Step 4

The compound (III) is subjected to dehydration in the same manner as Method A (step 2) to prepare the compound (Ia).

METHOD D Step 1

The compound (II) is reacted with N-protected-β-alanine, in the presence of condensing agent such as 1,3-dicyclohexylcarbodiimide, and 1-hydroxybenzotriazole in an appropriate organic solvent to prepare the compound (IV).

The reaction is performed at a temperature of from 10° to 150° C., preferably from room temperature to 70° C., for 1-20 hours, especially for 3-7 hours.

The same organic solvent as mentioned in METHOD A (Step 1) may be used.

Step 2

The compound (IV) is reacted in an appropriate solvent to remove the amino-protecting group. Then the obtained compound is subjected to a reduction reaction in the presence of a reductant.

The former reaction is performed at a temperature of from 10° to 150° C., preferably from room temperature to 70° C., for 1-20 hours, especially for 3-7 hours.

The same organic solvent as mentioned in METHOD A (Step 1) may be used, most preferably trifluoroacetic acid.

The latter reduction reaction is performed in an ordinary method in the presence of the reductant such as lithium aluminium hydride, hydro iodide, hydrogen sulfide, and sodium iodide at a temperature of from 0° and 100° C., preferably room temperature, for 1 to 7 hours, especially for 2 to 4 hours.

Step 3

The compound (V) is reacted with RH (VIII) to prepare the compound (Ia).

The reaction is performed at a temperature of from 50° to 200° C., preferably from 100° to 130° C., for 30 minutes to 5 hours, especially for 1-3 hours.

The compound of the present invention can be administered orally or parenterally. For example, the compound of the present invention may be orally administered in the form of tablets, powders, capsules, and granules, or liquid form such as syrup or elixir, and parenterally in the form of injection of an aqueous or oily suspension.

These preparations can be prepared in a conventional manner by using excipients, binders, lubricants, aqueous or oily solubilizers, emulsifier, suspending agents, and the like. And further additives such as preservatives and stabilizers can be used.

The dosages may be varied depending upon the administration route age, weight and condition of the patient, and the kind of disease but is, usually 5-1000 mg/day, preferably 20-200 mg/day through the oral route, and 1-500 mg/day, preferably 5-50 mg/day through the parenteral route in a single or divided doses.

The present invention is illustrated by the following examples and reference examples, which are not to be considered as limiting.

The abbreviations used in examples and reference examples have the following meanings.

Me: methyl, Et: ethyl, t-Bu: tert-butyl, iPr: isopropyl, Ph: phenyl, Ts: tosyl DMF: dimethylformamide, aq.: aqueous

EXAMPLE 1 1-[3-{4-(3,4-dichlorophenyl)-1,2,5,6-tetrahydropyridin-1-yl}-propylcarbamoyl]-2-oxopyrrolidine (I a-1) ##STR4##

(1) A solution of 3.0 g of 4-hydroxy-4-(3,4-dichlorophenyl)piperidine (II-1) and 2.50 g of 1{(3-chloropropyl)carbamoyl-2-oxopyrrolidine in 35 ml of DMF is stirred at 105°-110° C. for 6 hours in the presence of 2.74 g of NaI and 4.22 g of K₂ CO₃ (reaction condition 1). The reaction mixture is poured into ice-water, and the solution is extracted with ethyl acetate. The organic layer is washed with water, dried over MgSO₄ and concentrated under reduced pressure. The obtained oily substance is subjected to column chromatography with silica gel; eluting with methylene chloride/methanol (15/1-10/1 v/v) to prepare 4.20 g of the objective compound (III-1) as colorless needles. mp.: 135.5°-137.0° C.

Anal Calcd. (%) for C₁₉ H₂₅ N₃ O₃ Cl₂ : :C, 54.90; H, 6.10; N, 10.16; Cl, 17.21. Found: C, 55.08; H, 6.08; N, 10.14; Cl, 17.11.

IR (CHCl₃): 3600, 3320, 1712, 1680, 1545, 1489, 1470

NMR (CDCl₃) δ (200 MHz): 1.682 (dd, J₁ =12 Hz, J₂ =2 Hz, 2H); 1.772 (quint, J=7 Hz, 2H); 2.042 (quint, J=8 Hz, 2H); 2.062 (s, 1H); 2.191 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.409 (t, J=11 Hz, 2H); 2.497 (t, J=7 Hz, 2H); 2.628 (t, J=8 Hz, 2H); 2.837 (dd, J₁ =11 Hz, J₂ =2 Hz, 2H); 3.394 (q, J=6 Hz, 2H); 3.854 (t, J=7 Hz, 2H); 7.393,7.401,7.716 (sx3,3H)

(2) A solution of 2.77 g of the compound (III-1) and 1.60 g of p-toluenesulfonic acid in 300 ml of toluene is refluxed for 48 hours to separate water as azeotropic mixture of toluene. After removal of the solvent, the residue is dissolved in ethyl acetate and washed with aq.NaOH and water. The solution is dried over Na₂ SO₄ and concentrated under reduced pressure. The oily residue is subjected to column chromatography with silica gel, eluting with ethyl acetate-methylene chloride/methanol (20/1 v/v) to prepare 2.26 g (Yield: 89.3%) of the objective compound (I a-1) as an oil. The maleate is recrystallized from i-PrOH to prepare 2.50 g colorless needles. mp. 135.5°-136.5° C.

Anal Calcd. (%) for C₁₉ H₂₃ N₃ O₂ Cl₂.C₄ H₄ O₄ : C, 53.84; H, 5.32; N, 8.18; Cl, 13.93. Found: C, 53.91; H, 5.31; N, 8.20; Cl, 13.84.

IR (Nujol) cm⁻¹ : 3310, 1713. 1680, 1625, 1580, 1550 (sh), 1518, 1485, 1455

NMR (CDCl₃) δ (200 MHz): 1.829 (quint, J=7 Hz, 2H); 2.039 (quint, J=8 Hz, 2H); 2.50˜2.55 (m, 4H); 2.612 (t, J=8 Hz, 2H); 2.714 (t, J=6 Hz, 2H); 3.171 (q, J=3.3 Hz, 2H); 3.398 (q, J=7 Hz, 2H); 3.874 (t, J=7 Hz, 2H); 6.100 (quint, J=2 Hz, 1H); 7.224 (dd, J₁ =8 Hz, J₂ =2 Hz, 1H); 7.397 (d, J=8 Hz, 1H); 7.463 (d, J=2 Hz, 2H); 8.513 (brs, 1H)

EXAMPLE 2-16

The reaction is performed in the same manner as Example 1 to prepare the compound (I a). The reaction conditions are shown in table 1 and 2, and physical constants of the compound (III) are shown in table 3 and those of the compound (I a) are shown in table 4.

                                      TABLE 1                                      __________________________________________________________________________     (Step 1)                                                                        ##STR5##                                                                      Ex.                                                                               (II)               DMF K.sub.2 CO.sub.3                                                                   NaI reaction                                                                              eluent    g (%)                       No.                                                                               X=   R(CH.sub.2)nY(VI)                                                                            (ml)                                                                               (g) (g) condition (1)                                                                         condition compd.                      __________________________________________________________________________                                                        No.                         2  CF.sub.3 (p) 2.50 g (II-2)                                                           ##STR6##     25  2.28                                                                               2.29                                                                               105-110 7 hr.                                                                         CH.sub.2 Cl.sub.2 /MeOH =                                                                3.89 (92.2) (III-2)         3  n-Pr (p) 2.25 g (II-3)                                                               ##STR7##     20  2.85                                                                               2.31                                                                               105 5 hr.                                                                             CH.sub.2 Cl.sub.2 /MeOH =                                                                2.98 (74.6) (III-3)         4  Et (p) 3.00 g (II-4)                                                                 ##STR8##     30  4.04                                                                               3.28                                                                               105 7 hr.                                                                             CH.sub.2 Cl.sub.2 /MeOH =                                                                4.10 (75.2) (III-4)         5  Ph (p) 4.76 g (II-5)                                                                 ##STR9##     57  5.19                                                                               4.22                                                                               105 24 hr.                                                                            CH.sub.2 Cl.sub.2 /MeOH =                                                      20/1-10/1 7.31 (92.3) (III-5)         6  t-Bu (p) 6.0 g (II-6)                                                                ##STR10##    60  7.11                                                                               5.78                                                                               105 10 hr.                                                                            CH.sub.2 Cl.sub.2 /MeOH =                                                                8.36 (81.0) (III-6)         7  n-Pr (p) 1.95 g (II-3)                                                               ##STR11##    30  2.46                                                                               2.0 105° C. 9 hr.                                                                  CH.sub.2 Cl.sub.2 /MeOH =                                                      20/1-10/1 2.0 (65.0) (III-7)          8  t-Bu (p) 1.98 g (II-6)                                                               ##STR12##    20  1.35                                                                               1.10                                                                               100° C. 2.6 hr.                                                                CH.sub.2 Cl.sub.2 /MeOH =                                                      19/1-9/1  0.853 (46.9) (III-8)        9  CF.sub.3 (p) 2.33 g (II-2)                                                           ##STR13##    30  2.62                                                                               2.14                                                                               100-105° C. 8.5                                                                CH.sub.2 Cl.sub.2 /MeOH =                                                      20/1-10/1 2.46 (65.0) (III-9)         10 Ph 930 mg (II-5)                                                                     ##STR14##    11   1.015                                                                              0.825                                                                             105° C. 5 hr.                                                                  CH.sub.2 Cl.sub.2 /MeOH/                                                       NH.sub.4 OH =  128/16/1-32/6/1                                                           0.616 (41.0) (III-10)       11 t-Bu (p) 844 mg (II-6)                                                               ##STR15##    11  1.00                                                                               0.813                                                                              100° C. 5.5 hr.                                                                CH.sub.2 Cl.sub.2 /MeOH/                                                       NH.sub.4 OH =  128/16/1-64/8/1                                                           0.830 (57.3) (III-11)       12 CF.sub.3 (m) 2.5 g (II-7)                                                            ##STR16##    25  2.76                                                                               2.25                                                                               100-105° C. 5.5                                                                CH.sub.2 Cl.sub.2 /MeOH =                                                                3.8 (90.2) (III-12)         13 CF.sub.3 (p) 527 mg (II-2)                                                           ##STR17##    7   0.59                                                                               --  105° C. 7 hr.                                                                  CH.sub.2 Cl.sub.2 /MeOH =                                                      20/1-10/1 0.82 (86.0) (III-13)        14 t-Bu (p) 2.03 g (II-6)                                                               ##STR18##    20  2.40                                                                               1.95                                                                               105° C. 7.5 hr.                                                                CH.sub.2 Cl.sub.2 /MeOH =                                                      20/1-7/1  2.99 (82.8) (III-14)        15 Me (p) 1.07 g (II-8)                                                                 ##STR19##    26  1.61                                                                               1.31                                                                               95° C. 7 hr.                                                                   CH.sub.2 Cl.sub.2 /MeOH =                                                      19/1-9/1  0.477 (24.8) (III-15)       16 t-Bu (p) 980 mg (II-6)                                                               ##STR20##    20  1.16                                                                               0.94                                                                               105° C. 6.5 hr.                                                                CH.sub.2 Cl.sub.2 /MeOH =                                                      10/1-5/1  1.69 (92.6) (III-16)        __________________________________________________________________________

                                      TABLE 2 (Step 2)                             __________________________________________________________________________     starting                eluenting condition                                                                          product                                  material                                                                            acid  solvent (ml)                                                                          reflux time                                                                          (2)           (g)                                      __________________________________________________________________________     (III-2)                                                                             TsOH.H.sub.2 O                                                                       toluene(280)                                                                          48 hr.                                                                               ethyl acetate-                                                                               Ia-2                                     4.24 g                                                                              (3.90 g)                                                                             dichloro-    CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                               2.26 g                                   (III-3)                                                                             CF.sub.3 COOH                                                                        --     10 hr.                                                                               toluene/      2 a-3                                    2.52 g                                                                              (25 ml)                                                                              --           ethyl acetate = 1/1                                                                          2.22 g                                                           CH.sub.2 Cl.sub.2 /MeOH = 20/1                         (III-4)                                                                             CF.sub.3 COOH                                                                        --     10 hr.                                                                               ethyl acetate-                                                                               Ia-4                                     4.10 g                                                                              (35 ml)            CH.sub.3 Cl.sub.3 /MeOH = 30/1-10/1                                                          3.41 g                                   (III-5)                                                                             CF.sub.3 COOH                                                                        --     9 hr. CH.sub.3 Cl.sub.3 /MeOH = 30/1-20/1                                                          Ia-5                                     2.73 g                                                                              (30 ml)                          2.40 g                                   (III-6)                                                                             CF.sub.3 COOH                                                                        --     4 hr. ethyl acetate-                                                                               Ia-6                                     2.08 g                                                                              (25 ml)            CH.sub.2 Cl.sub.2 /MeOH = 30/1-20/1                                                          1.90 g                                                                         (95.6)                                   (III-7)                                                                             CF.sub.3 COOH                                                                        --     7.5 hr.                                                                              toluene/ethyl-                                                                               Ia-7                                     2.67 g                                                                              (30 ml)            ethyl acetate = 1/1-                                                                         0.24 g                                                           ethyacetate   (59.8)                                   (III-8)                                                                             CF.sub.3 COOH                                                                        --     1.8 hr.                                                                              toluene/acetone = 2/1                                                                        Ia-8                                     0.822 g                                                                             (2 ml)                                                                               --           CH.sub.2 Cl.sub.2 /MeOH = 9/1                                                                0.697 g                                                                        (88.8)                                   (III-9)                                                                             CF.sub.3 COOH                                                                        --     24.5 hr.                                                                             toluene/      Ia-9                                     2.27 g                                                                              (25 ml)            ethyl acetate = 1/1                                                                          1.13 g                                                           CH.sub.3 Cl.sub.2 /MeOH = 20/1-10/1                                                          (52.1)                                   (III-10)                                                                            CF.sub.3 COOH                                                                        --     1 hr. CH.sub.2 Cl.sub.2 /MeOH = 9/1                                                                Ia-10*                                   0.766 g                                                                             (10 ml)                          0.572 g                                                                        (60.5)                                   (III-11)                                                                            CF.sub.3 COOH                                                                        --     1 hr. CH.sub.2 Cl.sub.2 /MeOH = 9/1                                                                Ia-11*                                   0.914 g                                                                             (10 ml)                          0.854 g                                                                        (75.4)                                   (III-12)                                                                            CF.sub.3 COOH                                                                        --     23 hr.                                                                               toluene/      Ia-12                                    3.42 g                                                                              (35 ml)            ethyl acetate = 1/1                                                                          3.15 g                                                           CH.sub.2 Cl.sub.2 /MeOH =  20/1                                                              (96.0)                                   (III-13)                                                                            CF.sub.3 COOH                                                                        --     72 hr.                                                                               toluene/      Ia-13                                    3.45 g                                                                              (45 ml)            ethyl acetate = 1/1                                                                          2.96 g                                                           CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                               (89.4)                                   (III-14)                                                                            CF.sub.3 COOH                                                                        --     5 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                               Ia-14                                    2.82 g                                                                              (35 ml)                          2.62 g                                                                         (97.0)                                   (III-15)                                                                            CF.sub.3 COOH                                                                        --     3 hr. toluene/acetone = 2/1                                                                        Ia-15                                    0.544 g                                                                             (1 ml)       (room               0.313 g                                             --     temper-             (59.6)                                                     ature)                                                       (III-16)                                                                            CF.sub.3 COOH                                                                        --     4 hr. toluene/      Ia-16                                    1.50 g                                                                              (20 ml)                                                                              --           ethyl acetate = 1/1                                                                          1.40 g                                                           CH.sub.2 Cl.sub.2 /MeOH = 20/1-10/1                                                          (97.4)                                   __________________________________________________________________________      *maleate                                                                 

    TABLE 3       Compd. mp. (°C.) Anal. Calcd. (%)   No. (solvent) Found (%) I R      (cm.sup.-1) NMR (δ)        III-2 151.5-152.5 C.sub.29 H.sub.26 N.sub.3 O.sub.3 F.sub.3       : (CHCl.sub.3) (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 --Et.sub.2 O) C.57.92      (58.10) 3600, 3310, 1713 1.712(d-d,J.sub.1 =12Hz, J.sub.2 =2Hz, 2H);      1.776(quint J=7Hz, 2H); 2.026  (CH.sub.2 Cl.sub.2 --Et.sub.2 O) H, 6.26      (6.34) 1680, 1605, 1510 quint, J=7Hz, 2H); 2.046(s, 1H); 2.210(t-d,      J.sub.1 =13Hz, J.sub.2 =4Hz, 2H);   N.10.15 (10.16) 1489 2.432(t-d,      J.sub.1 =11Hz, J.sub.2 =2Hz, 2H); 2.490(t, J=7Hz, 2 H); 2.601   F,1357      (13.79)  (t, J=8Hz, 2H); 2.838(d-d, J.sub.1 =11Hz, J.sub.2 =2Hz, 2H);      7.595(d, J=8Hz,     2H); 7.679(d, J=8Hz, 2H); 8.619(brs. 1H) III-3      96.0-97.0 C.sub.22 H.sub.33 N.sub.3 O: (CHCl.sub.3) (CDCl.sub.3)      (ethyl- C, 67.84 (68.18) 3600, 3320, 1713 1.634(sextet, J=7Hz, 2H);      1.70˜1.85(m, 4H); 2.018(quint, J=8Hz,  acetate-Et.sub.2 O H, 8.41      (8.58) 1680, 1602, 1547 2H); 2.185(t-d), J.sub.1 =13Hz, J.sub.2 =4Hz,      2H); 2.38˜2.64(m, 8H); 7.160   N, 10.74 (10.84 1490, 1460 (d,      J=8Hz, 2H); 7.343 (d, j=8Hz, 2H); 8.551(brs. 1H) III-4 84.0-85.5      (CHCl.sub.3) (CDCl.sub.3)    3600, 3320, 1713 1.235(t, J=8Hz, 3H);      1.72˜1.83(m, 4H); 2.022(quint, J=7Hz, 2H);    1680, 1545 2.191(t-d)      , J.sub.1 13Hz, J.sub.2 =4Hz, 2H); 2.4˜2.7(m, 8H); 2819(d-d,      J.sub.1 =     12Hz, J.sub.2 =1Hz, 2H); 3.375(q, J=6Hz, 2H); 3.848(t,      J=7Hz, 2H); 7.1     86(d, J=8Hz, 2H); 7.442(d, J=8Hz, 2H); 8.555(brs.      1H) III-5 155.5-156.5 C.sub.26 H.sub.31 N.sub.3 O.sub.3.1/5H.sub.2 O      (CHCl.sub.3) (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 --Et.sub.2 O C, 70.50      (70.63) 3600, 3320, 1713 1.84˜1.73(m, 4H); 2.014(quint, J=8Hz,      2H); 2.247(t-d, J.sub.1 =14Hz,   H, 7.46(7.82 1682, 1545 J.sub.2 = 4Hz,      2H); 2,458(t-d, J.sub.1 =14Hz, J.sub.2 1H, 2H); 2H); 2.507(t, J=7Hz,      2H);   N, 965 (9.88)  2.595(t, J=8Hz, 2H); 2.853(d, J=11Hz, 2H);      3.386(q, J=6Hz,     2H); 3.846(t,J =7Hz, 2H); 7.25˜7.65 (m, 9H);      8.577(brs. 1H) III-6 149.5-150.5 C.sub.23 H.sub.36 N.sub.3 O.sub.3      (CHCl.sub.3) (CDCl.sub.3)  (CH.sub.3 Cl.sub.2 --Et.sub.2 O) C, 68..48      (68.80) 3600, 3320, 1713 1.303(s, 9H); 1.521(s, 1H); 1.738(d-d, J.sub.1      =11Hz, J.sub.2 =3Hz, 2H);   H, 8.69 (8.79) 1680, 1543 1.793(quint,      J=8Hz, 2H); 2.022(quint, J=7Hz, 2H); 2.195(t-d, J.sub.1 =13Hz,   N,      10,39(10.46)  J.sub.2 =4Hz, 2H); 2.39˜2.53(m, 4H); 2.593(t, J=8Hz,      2H); 2.823     (d, J=11Hz, 2H); 3.375(q. J=7Hz, 2H); 3.851(t, J=7Hz,      2H); 7.38,     7.43(ABq, J=9Hz, 4H); 8.543(brs, 1H) III-7 161.0˜162      .5 C.sub.22 H.sub.33 N.sub.2 O.sub.3 Cl.1/2H.sub.2       O (Nujol) (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 - C, 63.46 (63.68) 3310,      2640, 2560 0.939(t, J=7Hz, 3H); 1.630(sextet, J=7Hz, 2H); 1.791(d,      J=12Hz,  (ethyl- H, 8.02 (8.18) 1730, 1680 2H); 1.87-2.10(m, 4H);      2.246(t-d, J.sub.1 =12Hz, J.sub.2       =3Hz, 2H); 2.50-  acetate) N, 6.83(6.75).sub.1  2.68(m, 8H); 2.920(d, J      =12Hz, 2H); 2.957(t, J=7Hz, 2H); 3.804   F, 7.98 (8.54)  (t, J=7Hz, 2H);      7.156, 7.406(ABq. J=8Hz, 4H) III-8 207.0-210.0 C.sub.23 H.sub.34 N.sub.2      O.sub.3: (CHCl.sub.3) (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 --Et.sub.2 O- C,      63.73 (71.47) 3663, 3598, 3345 1.299(s, 9H); 1.960(d, J=14Hz, 2H);      1.95-2.13(m, 4H); 2.17-2.35  n-hexane) H, 8.09 (8.87) 2630, 2460, 2410      (m, 2H); 2.606(t, J=8.hz, 2H); 2.694(t-d, J.sub.1 =14Hz, J.sub.2 2Hz,      2H);   N, 7.31 (7.25) 1740, 1692, 1611 2.95-3.10(m, 4H); 3.25-3.45(m,      4H); 3.800(t, J=7Hz, 2H); 7.368.    1509, 1471, 1460 7.441(ABq, J=8Hz,      4H) III-9 147.0˜148.0 C.sub.20 H.sub.23 N.sub.2 O.sub.3       F.sub.3.1/5H.sub.2 0 3600, 1738, 1693 (CDCl.sub.3)  (CH.sub.2 Cl.sub.2      -- Et.sub.2 O) C, 59.79 (59.75) 1620 1.715(d-d, J.sub.1 =14Hz, J.sub.2      =2Hz, 2H); 1.878(s, 1H); 1.898(quint, J=8   H, 6.27 (6.97)  Hz, 2H);      2.021(quint, J=8Hz, 2H); 2.152(t-d, J.sub.1 =14Hz, J.sub.2 =4Hz, 2H);      N, 6.79 (6.37)  2.451(t-d, J.sub.1 =15Hz, J.sub.2 =2Hz, 2H); 2.482(t,      J=8Hz); 2.584   F, 14.26 (14.18)  (t, J=8Hz, 2H); 2.862 (d, J=15Hz, 2H);      2.936(t, J=7Hz, 2H); 3.794     (t, J=8Hz, 2H) 7.579, 7.627 (ABz, J=8Hz,      4H) III-10 225.0˜228.0 C.sub.25 H.sub.33 N.sub.3       O.sub.2.1/10H.sub.2 O (Nujol) (CDCl.sub.3)  (CH.sub.2 Cl.sub.2       --MeOH--Et.sub.2 O) C, 73.25 (73.35) 3300, 3055, 3030 1.775(quint,      J=7Hz, 2H); 1.845(d, J=14Hz, 2H); 2.89-1.96(m, 4H);   H, 8.26 (8.18)      1606, 1528, 1487 2.171 (t-d, J.sub.1 =13Hz, J.sub.2       =4Hz, 2H); 2.52-2.63(m, 4H); 2.900(d,   N, 1021 (10.27) 1471, 1456,      1448 J=12Hz, 2H); 3.25-3.38(m, 4H); 7.30-7.70(m, 9H) III-11 138.5˜1      40.5 C.sub.23 H.sub. 37 N.sub.3 O.sub.2.2/5H.sub.2       O (Nujol) (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 --Et.sub.2 O) C, 70.07      (69.98) 3350, 3150, 1631 1.322(s, 9H); 1.76-1.94(m, 8H); 2.262(t-d,      J.sub.1 =14Hz, J.sub.2 =4Hz, 2H);   H, 9.54 (9.65) 1542, 1509, 1485      2.50-2.65(m, 4H); 2.951(d, J=11Hz, 2H); 3.30-3.39(m, 4H);   N, 10.66      (10.64) 1460, 1441, 1388 5.738(brs, 1H); 7.378, 7.418(ABz. J=8Hz, 4H)      III-12 113.5˜114.5 C.sub.20 H.sub.26 N.sub.3 O.sub.3 F.sub.3 :      (CHCl.sub.3) (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 --Et.sub.2 O) C, 57.90      (58.10) 3600, 3320, 1713 1.715 (d-d, J.sub.1 =12Hz, J.sub.2 =2Hz, 2H);      2.780(quintJ=7Hz, 2H); 2.000)   H, 6.26 (6.34) 1680, 1545, 1490 (s, 1H);      2.027(quint, J=7Hz, 2H); 2.253(t-d, J.sub.2 =13Hz, J.sub.2 =4Hz, 2H);      N, 10.14 (10.16) 1385, 1332 2.442(d, J=12Hz, 2H); 2.504(t, J=7Hz, 2H);      2.606(t, J=8Hz, 2   F, 13.49 (13.79)  H);2.854(d-d, J.sub.1 =11Hz,      J.sub.2 =3Hz, 2H); 3.394(quint, J=7Hz, 2H);     3.850(t, J=7Hz, 2H);      7.474(d, J=7Hz, 1H); 7.492(t, J=7Hz, 1H);     7.746(d, J=7Hz, 1H);      7.871(s, 1H); 8.678(brs, 1H) III-13 oil -- -- (CDCl.sub.2)     1.30-1.44(      m, 2H); 1.584(quint×2, J=7Hz, 4H); 1.747(d, J=12Hz, 2     H);      2.022(quint, J=7Hz, 2H); 2.216(t-d, J.sub.1 =13Hz, J.sub.2 =4Hz, 2H);       2.41-2.49(m, 4H); 2.600(t, J=8Hz, 2H); 2.773(d, J=11Hz, 2H); 3.292      (q, J=7Hz, 2H); 3.837(t, J=7Hz, 2H); 7.598, 7.662(ABz, J=9     Hz, 4H);      8.428(brs, 1H) III-14 153.0˜154.0 C.sub.24 H.sub.37 N.sub.3      O.sub.3 : (CHCl.sub.3) (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 --Et.sub.2 O) C,      69.29 (69.36) 3600, 3280, 1702 1.319(s, 9H); 1.623(s, 1H); 1.71-1.86(m,      8H); 2.190(t-d, J.sub.1 =13   H, 8.93 (8.97) (sh), 1697, 1645 Hz,      J.sub.2 =4Hz, 2H); 2.39-2.58(m, 6H); 2.824(d, J=11Hz, 2H); 3.375   N,      10.14 (10.11) 1530, 1480, 1460 (q, J=7Hz, 2H); 3.75-3.82(m, 2H); 7.463,      7.372(ABz, J=9Hz, 4H);    1400 9.479(brs, 1H) III-15 ˜180 -- --      (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 --Et.sub.2 O)   1.782(d-d, J.sub.1      =14Hz, J.sub.2 =2Hz, 2H); 1.90-2.12(m, 6H); 2.275(t-d,     J.sub.1      =14Hz, J.sub.2 =2Hz, 2H); 2.330(s, 3H); 2.600(t, J=8Hz, 4H); 2.965      (t, J=7Hz, 4H); 3.810(t, J=7Hz, 2H); 7.163, 7.394(ABz, J=8Hz, 4H) III-16      129.0˜130.5 C.sub.28 H.sub.41 N.sub.3 O.1/3H.sub.2 O (CHCl.sub.3)      (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 --Et.sub.2 O) C, 76.08 (76.15) 3600,      1602, 1580 1.661(s, 1H); 1.77-1.94(m, 4H); 2.285(t-d, J.sub.1 =13Hz,      J.sub.2 =2Hz, 2H);   H, 9.41 (9.51) 1505(sh), 1495 2.460(t, J=7Hz, 2H);      2.53-1.65(m, 6H); 3.18-3.24(m, 2H);   N, 9.63 (9.51) 1470, 1460(sh),      680-7.48(m, 9H)    1455, 1400, 1380

    TABLE 4       Compd. mp. (°C.) Anal Calcd. (%)   No. (solvent) Found (%) IR      (cm.sup.-1) NMR (δ)        Ia-2 187.0-188.5 C.sub.20 H.sub.24 N.sub.3 O.sub.2 F.sub.3.C.sub.2      H.sub.2 O.sub.4 (CHCl.sub.3) (CDCl.sub.3 -CD.sub.3 OD=1/5)  (oxalate) C,      54.45 (54.43) 3290, 2600 (br), 2.00˜2.20(m, 4H); 2.620(t, J=8Hz,      2H); 2.98˜2.87(brs, 2H); 3.29  (i-PrOH) H, 5.38 (5.40) 1710, 1685,      1615 2(t, J=8Hz, 2H); 3.451(t, J=7Hz, 2H); 3.556(t, J=6Hz, 2H); 3.81      N, 8.76 (8.66) 1550, 1460 9(t, J=7Hz, 2H); 3.977(d, J=3Hz, 2H); 6.239(t,      J=3Hz, 1H); 7.64   F, 12.26 (11.74)  6(s, 4H) Ia-3 162.0-162.5 C.sub.26      H.sub.35 N.sub.3 O.sub.6 : (Nujol) (CDCl.sub.3)  (maleate) C, 64.23      (64.31) 3330, 1705 (s), 0.935(t, J=7Hz, 3H); 1.629(sextet, J=7Hz, 2H);      1.828(quint, J=  (i-PrOH) H, 7.23 (7.27) 1695, 1620, 1575 7Hz, 2H);      2.015 (quint, J=7Hz, 2H); 2.49˜2.64(m, 8H); 2.706 (t,   N, 8.54      (8.65) 1528 J=6Hz, 2H); 3.158(q, J=3Hz, 2H); 3.387(q, J=7Hz, 2H);      3.858(t,     J=7Hz, 2H); 6.032(quint, J=2Hz, 1H); 7.117(d, J=8Hz, 2H);      7.302     (d, J332 8Hz, 2H); 8.486(brs, 1H) Ia-4 86.0-87.0 C.sub.27      H.sub.29 N.sub.3 O.sub.2 (CDCl.sub.3) (CDCl.sub.3)  (ether) C, 70.97      (70.95) 3220, 1713, 1682 1.227(t, J=7Hz, 3H); 1.824(quint, J=7Hz, 2H);      2.015(quint, J=7   H, 8.11 (8.22) 1545, 1488, 1460 (Hz, 2H); 2.527(t,      J=8Hz, 2H); 2.561(brs, 2H); 2.591(t, J=8Hz,   N, 11.97 (11.82)  2H);      2.629(q, J=8Hz, 2H); 3.150(q, J=3Hz, 2H); 3.386(q, J=7Hz,     2H);      3.856(t, J=7Hz, 2H); 6.017(quint, J=2Hz, 1H); 7.141(d, J=     8Hz, 2H);      7.310(d, J=8Hz, 2H); 8.490(brs. 1H) Ia-5 144.0-146.0 C.sub.25 H.sub.29      N.sub.3 O.sub.2 (CHCl.sub.3) (CDCl.sub.3)  (decom. C, 74.32 (74.41)      3320, 1702, 1680 1.840(quint, J=7Hz, 2H); 2.019(quint, J=8Hz, 2H);      2.555(t, J=8  point) H, 7.21 (7.24) 1600, 1545, 1485 Hz, 2H); 2.584(br,      2H); 2.596(t, J=8Hz, 2H); 2.733(t, J=6Hz, 2H);  (ethyl N, 10.49 (10.41)      3.190(q, J=3Hz, 2H); 3.398(q, J=7Hz, 2H); 3.863(t, J=7Hz, 2H);  acetate)        6.128(quint, J=3Hz, 1H); 7.26˜7.63(m, 9H); 8.504(brs, 1H) Ia-6      173.0-174.0 C.sub.23 H.sub.33 N.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4      (Nujol) (CDCl.sub.3)(free)  (decom.) C, 64.68 (64.91) 3320, 1712, 1690      1.314(s, 9H); 1.837(quint, J=7Hz, 2H); 2.022(quint, J=7Hz, 2H);      (maleate) H, 7.48 (7.46) 1620, 1580, 1543 2.5˜2.6(m, 6H); 2.717(t,      J=6Hz, 2H); 3.169(q, J=3Hz, 2H); 3.387  (i-PrOH--MeOH) N, 8.38 (8.41)      (q, J=6Hz, 2H); 6.023(q, J=2Hz, 1H), 1H); 7.332(s, 4H); 8.496(brs.      1H) Ia-7 190.0-191.0 C.sub.20 H.sub.24 N.sub.3 O.sub.2 F.sub.3.C.sub.2      H.sub.2 O.sub.4 (Nujol) (CDCl.sub.3)  (oxalate) C, 64.39 (64.85) 2500,      1732, 1725 0.935(t, J=7Hz, 3H); 1.629(sextet, J=8Hz, 2H); 1.978(sextet,      J=  (MeOH) H, 7.27 (7.26) (sh), 1685, 1610 7Hz, 2H); 1.989(sextet,      J=7Hz, 2H); 2.52-2.60(m, 8H); 2.745(t,   N, 6.12 (6.30) (br) J=6Hz, 2H);      2.973(t, J=7Hz, 2H); 3.195(q, J=3Hz, 2H); 3.795(t,     J=7Hz, 2H);      6.022(quint, J=2Hz, 1H); 7.120, 7.299(ABz, J=8Hz, 4H) Ia-8 96.0-97.0      C.sub.23 H.sub.32 N.sub.2 O.sub.2: (CHCl.sub.3) (CDCl.sub.3)  (Et.sub.2      O-- C, 76.23 (74.96) 1737, 1692, 1508 1.317(s, 9H); 1.962(sextet, J=6Hz,      2H); 1.996(sextet, J=6Hz, 2H);  n-hexane) H, 8.73 (8.75) 1482, 1459,      1427 2.570(q, J=8Hz, 6H); 2.721(t, J=5Hz, 2H); 2.972(t, J=7Hz, 2H);   N,      7.65 (7.60) 1364 3.174(q, J=3Hz, 2H); 3.801(t, J=7Hz, 2H); 6.031(quint,      J=2     Hz, 1H); 7.331(s, 4H) Ia-9 149.5-150.5 C.sub.20 H.sub.23 N.sub.2      O.sub.2 F.sub.3 (CHCl.sub.3) (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 -- C,      63.17 (63.15) 1738, 1692, 1615 1.964(sextet, J=7Hz, 2H); 2.001(sextet,   7      J=Hz, 2H); 2.538(q, J=  Et.sub.2 O) H, 6.09 (6.09) 1477, 1365, 1325 8Hz,      6H); 2.745(t, J =6Hz, 2H); 2.980(t, J=7Hz, 2H); 3.207(q, J=   N, 7.38      (7.36)  3Hz, 2H); 3.803(t, J=7Hz, 2H); 6.160(quint, J=3Hz, 1H); 7.472,      F, 1506 (14.98)  7.565(ABq, J=8Hz, 4H) Ia-10 164.0-166.0 C.sub.25      H.sub.31 N.sub.3 O.C.sub.4 H.sub.4 O.sub.4 (Nujol) (CD.sub.3 OD)      (malenate) C, 68.89 (68.89) 3403, 3037, 2330 1.88-2.06(m, 4H); 2.951(brs,       2H); 3,29-3.40(m, 6H); 3.557(brs,  (MeOH--Et.sub.2 O) H, 6.97 (6.98)      1700, 1640, 1578 2H); 3.959(brs, 2H); 6.220(s, 1H); 6.248(s, 2H);      7.30-7.70(m, 9H)   N, 8.30 (8.31) 1537, 1498, 1457 Ia-11 138.0-140.0      C.sub.23 H.sub.35 N.sub.3 O.C.sub.4 H.sub.4 O.sub.4. (Nujol) (CD.sub.3      OD)  (malenate) 1/5H.sub.2 O 3522, 3362, 2718 1.316(s,9H); 1.87-2.08(m,      6H); 2.896(brs, 2H); 3.22-3.36(m,  (MeOH--Et.sub.2 O) C, 66.16 (66.29)      2350, 1701, 1630 8H); 3.526(brs, 2H); 3.918(brs, 2H); 6.117(quint,      J=3Hz, 1H);   H, 8.21 (8.12) 1579, 1524, 1498 6.245(s, 2H); 7.414(s, 4H)        N, 8.82 (8.59) Ia-12 128.0-129.0 C.sub.20 H.sub.24 N.sub.3 O.sub.2      F.sub.3. (Nujol) (CDCl.sub.3)  (malenate) C.sub.4 H.sub.4 O.sub.4 3300,      2300 (br), 1.831(quint, J       =7Hz, 2H); 2.027(quint, J=8Hz, 2H); 2.51-2.65(m,  (i-PrOH--MeOH) C,      56.35 (56.36) 1710, 1638, 1625 6H); 2.729(t, J=6Hz, 2H); 3.186(q, J=3Hz,      2H); 3.397(q, J=7Hz,   H, 5.55 (5.52) 1570, 1530, 1500 2H); 3.865(t,      J=7Hz, 2H); 6.145(quint, J=2Hz, 1H); 7.41-7.63(m,   N, 8.21 (8.22) 1460,      1445 4H); .517 (brs. 1H)   F, 11.08 (11.14) Ia-13 128.0-129.5 C.sub.22      H.sub.28 N.sub.3 O.sub.2 F.sub.3. (Nujol) (CDCl.sub.3)  (oxalate)      C.sub.2 H.sub.2 O.sub.4.1/2PrOH 3510, 3310, 1708 1.35-1.47(m, 2H);      1.613(quint×2, J=7Hz, 4H); 2.025(quint, J=8  MeOH--i-PrOH) C,      56.18 (56.35) 1690, 1680, 1615 Hz, 2H); 2.44-2.65(m, 6H); 2.716(t,      J=5Hz, 2H); 3.181(q, J=3Hz,   H, 6.23 (6.39) 1537, 1480, 1460 2H);      3.312(q, J=6Hz, 2H); 3.862(t, J=7Hz, 2H); 6.157(quint, J=2   N, 7.70      (7.73)  Hz, 1H); 7.472, 7.563(ABz, J=8Hz, 4H); 8.419(brs. 1H) Ia-14      185.0-186.5 C.sub.24 H.sub.35 N.sub.3 O.sub.2.C.sub. 4 H.sub.4 O.sub.4      (Nujol) (CDCl.sub.3)  (malenate) C, 65.53 (65.48) 3285, 1695, 1648      1.312(s, 9H); 1.77-1.88(m, 6H); 2.49-2.56(m, 6H); 2.704(t, J=6  (MeOH)      H, 7.62 (7.65) 1620, 1580, 1523 Hz, 2H); 3.160(q, J=3Hz, 2H); 3.380(q,   7      J=Hz, 2H); 3.76-3.82(m,   N, 8.24 (8.18) 1477, 1460, 1450 2H); 6.026(quin      t, J=2Hz, 1H); 7.328(s, 4H); 9.444(brs, 1H) Ia-15 109.5-110.0 C.sub.20      H.sub.26 N.sub.2 O.sub.2 (CHCl.sub.3) (CDCl.sub.3)  Et.sub.2 O-- C,      73.79 (73.59) 1738, 1692, 1512 1.939(quint, J=7Hz, 2H); 2.007(quint,      J=7Hz, 2H); 2.328(s, 3H);  n-hexane) H, 8.08 (8.03) 1485, 1460, 1430      2.49-2.63(m, 4H); 2.713(t, J=5Hz, 2H); 2.969(t, J=7Hz, 2H); 3.153   N,      8.55 (8.58) 1367 (q, J=3Hz, 2H); 3.794(t, J=7Hz, 2H); 6.018(quint,      1=2Hz, 1H);     7.115, 7.280(ABz, J=8Hz, 4H) Ia-16 105.0-106.0 C.sub.28      H.sub.39 N.sub.3 O.sub.2.C.sub.4 .sub.4 O.sub.4 (Nujol) (CDCl.sub.3)      (malenate) C, 66.49 (66.54) 7710, 1622, 1598 1.315(s, 9H); 1.78-1.84(m,      8H); 2.43-2.75(m, 8H); 3.16- 3.25(m,  (i-PrOH--Et.sub.2 O) H, 7.26      (7.29) 1575, 1495(sh), 6H); 6.043(quint, J=2Hz, 1H); 6.80-7.34(m, 9H)      210.0-212.5 N, 6.59 (6.47) 1480, 1462, 1450  (MeOH)  1385, 1360

EXAMPLE 17 1-[4-{4-(4-trifluoromethylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}-butylcarbamoyl]-2-oxopyrrolidine (I a-17) ##STR21##

(1) A solution of 2.00 g of 4-hydroxy-4-(4-trifluoromethylphenyl)piperidine (II-2) and 2.42 g of phthalimido butyl bromide in 20 ml of DMF in the presence of 2.26 g of K₂ CO₃ is stirred at 105° C. for 6 hours. The reaction mixture is poured into ice-water, and the solution is extracted with ethyl acetate. The organic layer is washed with water, dried over Na₂ SO₄ and concentrated under reduced pressure. The obtained residue is subjected to column chromatography with silia gel eluting with methylene chloride/methanol (20/l v/v). The purified substance is recrystallized from methylene chloride/ether to prepare 3.0 g of the compound (IV-1). mp. 139.0°-140.5° C.

Anal Calcd. (%) for C₂₄ H₂₅ N₂ O₃ F₃ : C, 64.23; H, 5.73; N, 6.10; F, 12.98. Found: C, 64.57; H, 5.64; N, 6.27; F, 12.77.

IR (CHCl₃): 3590, 1772, 1713, 1618, 1470, 1440, 1409(sh), 1389

NMR (CDCl₃) (200 MHz) δ: 1.52-1.80 (m, 6H); 1.843 (s, 1H); 2.152 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.37-2.50 (m, 4H); 2.838 (dd, J₁ =9 Hz, J₂ =2 Hz, 2H); 3.728 (t, J=7 Hz, 2H); 7.613, 7.640 (ABq, J=9 Hz, 4H) 7.7-7.9 (m, 4H)

(2) A solution of 2.56 g of the compound (IV-1) and 424 mg of hydrazine hydrate in 25 ml of ethanol is refluxed for 3 hours. After the excess agent is distilled off under reduced pressure, the residue is mixed with 1.15 g of 1-phenoxycarbonyl-2-oxopyrrolidine and heated at 105° C. for 1.5 hours. The reaction mixture is subjected to column chromatography with silica gel eluting with methylene chloride/methanol=20/1-10/1 v/v. The obtained material is recrystallized from methylene chloride-ether to prepare 1.76 g (Yield: 73.5%) of the objective compound (III-17) as colorless needles. mp. 150.5°-152.0° C.

Anal Calcd. (%) for C₂₁ H₂₈ N₃ O₃ F₃ : C, 58.78; H, 6.51; N, 9.75; F, 13.56, Found: C, 59.01; H, 6.60; N, 9.83; F, 13.33.

IR (CHCl₃): 3590, 3320, 1713, 1680, 1618, 1545, 1489, 1460, 1409, 1385, 1328

NMR (CDCl₃): 1.57-1.63 (m, 4H); 1.743 (d, J=12 Hz, 2H); 2.019 (quint, J=7 Hz, 2H); 2.189 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.341 (s, 1H); 2.42-2.55 (m, 4H); 2.595 (t, J=8 Hz, 2H); 2.862 (dd, J₁ =10 Hz, J₂ =2 Hz, 2H); 3.311 (q, J=6 Hz, 2H); 3.822 (t, J=7 Hz, 2H); 7.591, 7.653 (ABq, J=9 Hz, 4H); 8.438 (brs, 1H)

(3) A solution of 1.40 g of the compound (III-17) in 20 ml of trifluoro acetic acid is refluxed for 72 hours. After removal of the excess reagent, the residue is poured into sodium hydroxide, and the solution is extracted with ethyl acetate. The organic layer is dried over MgSO₄ and concentrated under reduced pressure. The oily residue is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol (20/1 v/v) and recrystallized from i-PrOH-ether to prepare 1.31 g (Yield: 97.7%) of the objective compound (I a-17) as needles. mp. 136.0°-136.5° C.

Anal Calcd. (%) for C₂₁ H₂₆ N₃ O₂ F₃ : C, 61.87; H, 6.49; N, 10.26; F, 13.87, Found: C, 61.60; H, 6.40; N, 10.26; F, 13.92.

IR (CHCl₃): 3310, 1713, 1680, 1615, 1545, 1487, 1458, 1385, 1327

NMR (CDCl₃) (200 MHz) δ: 1.55-1.67 (m, 4H); 2.031 (quint, J=8 Hz, 2H); 2.47-2.65 (m, 6H); 2.725 (t, J=5 Hz, 2H); 3.190 (q, J=3 Hz, 2H); 3.344 (q, J=6 Hz, 2H); 3.857 (t, J=8 Hz, 2H); 6.156 (quint, J=2 Hz, 1H); 7.471, 7.564 (ABq, J=8 Hz, 4H); 8.436 (brs, 1H)

EXAMPLE 18 1-[N-propyl-N-[3-{4-(4t-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}-propylcarbamoyl]]-2-oxopyrrolidine (I a-18) ##STR22##

(1) A solution of 2.00 g of the compound (II-6) and 1.42 g of 3-bromo-1-chloropropane in 30 ml of DMF is stirred in the presence of 2.37 g of K₂ CO₃ at room temperature for 3.5 hours. The reaction mixture is poured into ice-water, and the solution is extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure to prepare 1.32 g of the compound (IV-2).

(2) A solution of 0.5 g of the compound (IV-2) and 0.44 ml of n-propyl in 1 ml of DMF is heated at 105° C. for 2 hours under stirring. The mixture is concentrated, and the residue is poured into aq.NaOH. The solution is extracted with methylene chloride, the organic layer is dried over MgSO₄ under reduced pressure. The oily residue is mixed with 310 mg of 1-phenoxycarbonyl-2-oxopyrrolidine and reacted at 115° C. for 2 hours. The reaction mixture is dissolved into methylene chloride, washed with aq. NaOH and aq.NaCl in order, dried over Na₂ SO₄, and concentrated under reduced pressure. The oily residue is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol (20/1-10/1 v/v) to prepare 500 mg (Yield: 70.0%) of the compound (III-18) as an oil.

IR (CHCl₃): 3595, 1720, 1665, 1605, 1517, 1465(sh), 1460, 1425, 1400, 1375

NMR (CDCl₃): 0.889 (t, J=7 Hz, 3H); 1.316 (s, 9H); 1.594 (q, J=8 Hz, 2H); 1.74-1.89 (m, 4H); 2.076 (quint, J=7 Hz, 2H); 2.207 (t, J=15 Hz, 2H); 2.435 (t, J=8 Hz, 2H); 2.48-2.60 (m, 4H); 2.80-2.90 (m, 2H); 3.317 (t, J=4 Hz, 2H); 3.421 (t, J=4 Hz, 2H); 3.712 (t, J=7 Hz, 2H); 7.368, 7.436 (ABq, J=8 Hz, 4H)

(3) A solution of 1.40 g of the compound (III-17) in 15 ml of trifluoroacetic acid is refluxed for 2.5 hours. The solution is concentrated, and the residue is poured into aq.NaOH. The solution is extracted with ethyl acetate, and the organic layer is dried over MgSO₄ and concentrated under reduced pressure. The oily residue is subjected to column chromatography with silica gel, eluting with toluene/ethyl acetate (1/1 v/v) to prepare 1.07 g (Yield: 80%) of the objective compound (I a-18) as an oil. mp. 158.5°-159.5° C. (dec.)

Anal Calcd. (%) for C₂₆ H₃₉ N₃ O₂.1/2 H₂ O: C, 64.38; H, 8.11; N, 8.05. Found: C, 64.10; H, 8.07; N, 8.01.

IR (Nujol): 3420, 2720, 2590, 2500, 1715, 1692, 1675(sh), 1610(br), 1515, 1460

NMR (CD₃ OD) (200 MHz)δ: 0.894 (t, J=7 Hz, 3H); 1.312 (s, 9H); 1.618 (q, J=7 Hz, 2H); 2.117 (quint, J=7 Hz, 4H); 2.458 (t, J=8 Hz, 2H); 2.872 (brs, 2H); 3.28-3.37 (m, 4H); 3.49-3.56 (m, 4H); 3.695 (t, J=7 Hz, 2H); 3.932 (brs, 2H); 6.089 (quint, J=2 Hz, 1H); 7.402 (s, 4H)

EXAMPLE 19

1-[3-{4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propyl]pyrrolidine (I a-19) ##STR23##

(1) A mixture of 10.061 g of the compound (II-6) and 5.41 ml of 3-chloro-1-propanol is stirred at 140° C. for 6 hours in the presence of 12.03 ml of Et₃ N. The reaction mixture is recrystallized from methylene chloride-ether-n-hexane to prepare 9.357 g (Yield: 74.0%) of the compound (IV-3). mp. 122.5°-123.5° C.

Anal Calcd. (%) for C₁₈ H₂₉ NO₂.1/10 H₂ O : C,73.72; H,9.93; N,4.82. Found: C,73.73; H,10.04; N,4.78.

IR (CHCl₃) cm⁻¹ : 3600, 3225, 1509, 1472, 1437, 1424, 1399, 1372 (sh), 1366

NMR (CDCl₃) δ: 1.31 (s, 9H); 1.62-1.85 (m, 4H); 2.119 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.507 (td, J₁ =12 Hz, J₂ =2 Hz, 2H); 2.707 (t, J=6 Hz, 2H); 2.973 (d, J=11 Hz, 2H); 3.829 (t, J=6 Hz, 2H); 7.367, 7.417 (ABq, J=8 Hz, 4H)

(2) A mixture of 10.568 g of the compound (IV-3) and 26.4 ml of thionyl chloride is stirred at room temperature overnight. Excess reagent is distilled off under reduced pressure, and the residue is poured into aq.Na₂ CO₃. The solution is extracted with methylene chloride, and the organic layer is dried over MgSO₄ and concentrated. The residue is subjected to column chromatography with silica gel, eluting with toluene/acetone (8/1-6/1 v/v) and recrystallized from n-hexane to prepare 2.167 g (Yield: 20.5%) of the compound (V-1) as colorless crystals.

Anal Calcd. (%) for C₁₈ H₂₆ NCl: : C, 73.86; H, 9.08; N, 4.96; Cl, 12.35. Found: C, 74.07; H, 8.98; N, 4.80; Cl, 12.15.

IR (CHCl₃): 1640, 1610, 1510, 1470, 1390, 1380

NMR (CDCl₃): 1.315 (s, 9H); 2.041 (quint, J=7 Hz, 2H); 2.50-2.66 (m, 4H); 2.714 (t, J=5 Hz, 2H); 3.169 (q, J=3 Hz, 2H); 3.638 (t, J=7 Hz, 2H); 6.032 (quint, J=3H, 1H); 7.334 (s, 4H)

(3) A mixture of 621 mg of the compound (V-1) and 1.78 ml of pyrrolidine is stirred at room temperature for 72 hours. The excess reagent is distilled off, and the residue is subjeced to column chromatography with silica gel, eluting with methylene chloride/methanol/ammonia (128/16/1 v/v) to prepare 675 mg of the compound (I a-19) as an oil, which is crystallized as maleate and recrystallized from methanol to give 800 mg (yield: 67.3%) of colorless plates. mp. 190.0°-191.0° C. (dec.)

Anal Calcd. (%) for C₂₂ H₃₄ N₂ O₂. C₄ H₄ O₄ : C, 64.74; H, 7.58; N, 5.11. Found: C, 64.50; H, 7.58; N, 5.01.

IR (Nujol): 2355, 1711, 1620, 1577, 1543, 1479(sh), 1461, 1378

NMR (CD₃ OD) δ: 1.314 (s, 9H); 2.122 (quint, J=3 Hz, 2H); 2.20-2.37 (m, 2H); 2.907 (brs, 2H); 3.30-3.43 (m, 6H); 3.567 (t, J=6 Hz, 2H); 3.949 (brs, 2H); 6.129 (brs, 1H); 6.269 (s, 2H); 7.416 (s, 4H)

EXAMPLE 20 1-[3-{4-(4-trifluoromethyl)-1,2,5,6-tetrahydropyridin-1-yl}-propyl]pyrrolidine (I a-20) ##STR24##

(1) A mixture of 5.00 g of the compound (II-2) and 2.22 ml of 3-chloro-1-propanol is stirred in the presence of 4.27 ml of Et₃ N at 140° C. for 8 hours. The mixture is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol/ammonium=64/8/1-32/6/1 v/v. The obtained purified substance is recrystallized from ether-n-hexane to prepare 5.155 g (Yield: 75.7%) of the compound (IV-4). mp. 116.0°-116.5° C.

Anal Calcd. (%) for C₁₅ H₂₀ NO₂ F₃ : C, 59.31; H, 6.59; N, 4.69; F, 18.70. Found: C, 59.40; H, 6.65; N, 4.62; F, 18.79.

IR (Nujol): 3335, 3075, 2773, 1617, 1462, 1436, 1407, 1378

NMR (CDCl₃) δ: 1.73-1.83 (m, 4H); 2.119 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.494 (td, J₁ =12 Hz, J₂ =3 Hz, 2H); 2.716 (t, J=6 Hz, 2H); 3.009 (d-d, J₁ =12 Hz, J₂ =2 Hz, 2H); 3.836 (t, J=6 Hz, 2H); 7.612 (s, 4H)

(2) The compound (IV-4) 4.892 g is treated in the same manner as Example 19(2) to prepare 3.357 g of the compound (V-2) as an oil.

IR (CHCl₃): 1608, 1453, 1439, 1399, 1368(sh), 1319

NMR (CDCl₃): 2.036 (quint, J=7 Hz, 3H); 2.54-2.62 (m, 2H); 2.636 (t, J=7 Hz, 2H); 2.733 (t, J=6 Hz, 2H); 3.192 (q, J=3 Hz, 2H); 3.635 (t, J=7 Hz, 2H); 6.152 (quint, J=2 Hz, 1H); 7.466, 7.562 (ABq, J=8 Hz, 4H)

(3) A mixture of 1.05 g of the compound (V-2) and 1.44 ml of pyrrolidine is stirred at room temperature for 32.5 hours, and the reaction mixture is treated in the same manner as Example 19 (3) to prepare 1.15 g (Yield: 98.2%) of the objective compound (Ia-20) as crystals. The malenate is recrystallized from methanol to prepare 1.04 g (Yield: 98.2%) of colorless needles. mp. 175.0-178.0 (dec.)

Anal. Calcd. (%) for C₁₉ H₂₅ N₂ F₃ O₂.C₄ H₄ O₄ : C, 57.92; H, 5.74; N, 4.97; F, 10.05. Found: C, 56.84; H, 5.83; N, 4.91; F, 9.99.

IR (Nujol): 2590, 2360, 2160, 1711, 1620, 1560, 1535(sh), 1483, 1458, 1378, 1359

NMR (CD₃ OD): 2.119 (quint, J=3 Hz, 4H); 2.20-2.37 (m, 2H); 2.92 7 (brs, 2H); 3.28-3.50 (m, 8H); 3.566 (t, J=6 Hz, 2H); 3.971 (q, J=2 Hz, 2H); 6.266 (s, 4H); 6.295 (brs, 1H); 7.681 (s, 4H)

EXAMPLE 21 1-[3-{4-(4-methylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}-propyl]pyrrolidine (Ia-21) ##STR25##

(1) A mixture of 10.20 g of the compound (II-8) and 5.51 ml of 3-chloro-1-propanol is stirred in the presence of 11 ml of Et₃ N at 140° C. for 5.5 hours. The reaction mixture is recrystallized from methylene chloride-ether to prepare 8.51 g (Yield: 64.0%) of the compound (IV-5). mp. 110.5°-111.5° C.

Anal Calcd. (%) for C₁₅ H₂₃ NO₂ : : C, 72.01; H, 9.25; N, 5.58. Found: C, 72.25; H, 9.30; N, 5.62.

IR (CHCl₃): 3597, 3220, 1513, 1470, 1452, 1437, 1423, 1397

NMR (CDCl₃) δ: 1.67-1.81 (m, 4H); 2.087 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.337 (s, 3H); 2.479 (td, J₁ =15 Hz, J₂ =3 Hz, 2H); 2.693 (t, J=6 Hz, 2H); 2.952 (d, J=11 Hz, 2H); 3.828 (t, J=5 Hz, 2H); 7.168, 7.372 (ABq, J=8 Hz, 4H)

(2) A solution of 12.82 g of the compound (IV-5) in 38 ml of trifluoroacetic acid is refluxed for 3.1 hours. The reaction mixture is concentrated, and the residue is poured into aq.NaHCO₃. The mixture is extracted with ethyl acetate, and the organic layer is dried over MgSO₄ and concentrated under reduced pressure. The oily substance is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol/NH₄ OH (128/16/1 v/v). A mixture of 870 mg of the product and 8.01 ml of thionyl chloride is stirred at room temperature for 2 hours. The excess reagent is distilled away under reduced pressure. The residue is washed with ether and dried under reduced pressure to give 1.067 g (Yield: 99.2%) of the objective compound (V-3) as a light yellowish powder.

IR (CHCl₃): 1600, 1510, 1460, 1410

NMR (CDCl₃): 2.046 (quint, J=7 Hz, 2H); 2.334 (s, 3H); 2.54, 2.64 (m, 2H); 2.629 (t, J=7 Hz, 2H); 2.723 (t, J=5 Hz, 2H); 3.173 (q, J=2 Hz, 2H); 3.630 (t, J=7 Hz, 2H); 6.023 (quint, J=2 Hz, 1H); 7.123, 7.287 (ABq, J=8 Hz, 4H)

(3) A mixture of 466 mg of the compound (V-3) and 0.78 ml of pyrrolidine is stirred at 50° C. for 3 hours and treated in the same manner as Example 19(3) to give the maleate of the objective compound (I a-21). It is recrystallized from methanol-iPrOH to prepare 225 mg (Yield: 42.5%) of the compound (I a-21) as needles. mp. 180.0°-181.0° C. (dec.)

Anal Calcd. (%) for C₁₉ H₂₈ N₂.2C₄ H₄ O₄ : : C, 62.84; H, 6.99; N, 5.48. Found: C, 62.78; H, 7.02; N, 5.42.

EXAMPLE 22-29

The compound (V-1), (V-2) and (V-3), each of which were obtained in Step 1 of Example 19-21, are reacted with amine (VIII) in the same manner as Step 3 in Example 19-21 to prepare the compound (I a). The reaction conditions and physical constants are shown in table 5 and 6.

                                      TABLE 5                                      __________________________________________________________________________      ##STR26##                                                                     Ex.     starting                  reaction  purification                                                                               product                No.     material RH               condition condition   mg                     __________________________________________________________________________                                                             (%)                    22      (V-1)    HN(i-Bu),        33 hours  CH.sub.2 Cl.sub.2 /MeOH                                                                     Ia-22.sup.*1                  0.628 g  3.76 ml          reflux    49/1-19/1   685 mg                                                                         (51.1%)                23      (V-2)    HN(i-Bu),        32 hours  CH.sub.2 Cl.sub.2 /MeOH =                                                                  Ia-23.sup.*1                   0.602 g  1.50 g           reflux    49/1-19/1   338 mg                                                                         (27.1%)                24      (V-3)    HN(i-Bu),        20 hours  CH.sub.2 Cl.sub.2 /MeOH                                                                    Ia-24.sup.*1                   0.517 g  1.36 g           reflux    49/1        457 mg                                                                         (38.4%)                25      (V-3) 0.924 g                                                                            ##STR27##       150° C. 8.15 hours                                                                toluene/ acetone                                                                            Ia-25.sup.*1                                                                  930 mg (54.4%)         26      (V-3) 0.624 g                                                                            ##STR28##       150° C. 4.1 hours                                                                 CH.sub.2 Cl.sub.2 /MeOH =                                                      19/1         Ia-26.sup.*1                                                                  963 mg (66.6%)         27      (V-2) 1.02 g                                                                             ##STR29##       100° C. 25 hours (in                                                              toluene/ acetone                                                                            Ia-27.sup.*1                                                                  266 mg (15.3%)         28      (V-2)    H,N-i-Bu         15.6 hours                                                                               CH.sub.2 Cl.sub.2 :MeOH:                                                                   Ia-28                          0.645 g  1.1 ml           reflux    NH.sub.4 OH                                                                                461 mg1                                                                        (63.8%)                29      (V-1) 0.828 g                                                                            ##STR30##       150° C. 3 hours                                                                   CH.sub.2 Cl.sub.2 /MeOH =                                                      29/1-19/1    Ia-29.sup.*1                                                                  773                    __________________________________________________________________________                                                             mg (70.2%)              .sup.*1 : separated as maleate                                                 .sup.*2 : prepared by the reaction with 492 mg of isoindoline and 162 mg       of 60% NaH in 5 ml of DMF at 100° C. for 1 hour.                  

                                      TABLE 6                                      __________________________________________________________________________     Compd.                                                                              mp. (°C.)                                                                        Anal Cald. (%)                                                   No.  Rec. sol..sup.*1                                                                        Found (%)   IR (cm.sup.-1)                                                                         NMR (δ) (200MHz)                       __________________________________________________________________________     I a-22                                                                              (maleate)                                                                               C.sub.26 H.sub.44 N.sub.2 O.sub.2.C.sub.4 H.sub.4 O.sub.4                                  (Nujol) (CD.sub.3 OD)                                     176.5˜178.0                                                                       C, 63.46 (63.68)                                                                           2620, 2510, 1690                                                                       1.083(d, J=7Hz, 12H); 1.314(s, 9H);                                            2.153(7tct. J=7Hz, 2H);                           (MeOH--Et.sub.2 O)                                                                      H, 8.02 (8.18)                                                                             1657, 1618, 1579                                                                       2.20-2.37(m, 2H); 2.913(brs, 2H);                                              3.042(d, J=7Hz, 4H);                              needleshaped                                                                            N, 6.83 (6.75)                                                                             1533, 1488, 1460                                                                       3.25-3.37(m, 4H); 3.588(t, J=6Hz, 2H);                                         3.974(s, 2H);                                     crystals F, 7.98 (8.54)                                                                             1409, 1378                                                                             6.131(s, 1H); 6.272(s, 4H); 7.419(s,                                           4H)                                          I a-23                                                                              (maleate)                                                                               C.sub.25 H.sub.35 N.sub.2 F.sub.3 O.sub.2.C.sub.4 H.sub.4                      O.sub.4     (Nujol) (CD.sub.3 OD)                                     135.0˜136.5                                                                       C, 59.12 (59.23)                                                                           2420, 1707, 1616                                                                       1.071(d, J=7Hz, 12H); 2.05-2.35(m, 4H);                                        2.90-3.30(m, 4H);                                 (MeOH--Et.sub.2 O)                                                                      H, 6.76 (6.89)                                                                             1572, 1485, 1456                                                                       3.20-3.30(m, 4H); 3.559(brs, 2H);                                              3.972(brs, 2H); J=7Hz, 2H);                       needleshaped                                                                            N, 4.35 (4.46)                                                                             1377    2.54-2.61(m, 2H); 2.747(t, J=5Hz, 2H);                                         6.260(s, 5H);                                     crystals F, 9.05 (9.07)                                                                             7.674(s, 4H)                                         I a-24                                                                              (maleate)                                                                               C.sub.23 H.sub.38 N.sub.2.C.sub.4 H.sub.4 O.sub.4                                          (Nujol) (CDCl.sub.3)                                      140.5˜142.5                                                                       C, 64.67 (64.79)                                                                           2710, 2500, 1706                                                                       0.872(d, J=7Hz, 12H); 1.685(quint,                                             J=7Hz, 4H); 2.059(d,                              (MeOH--Et.sub.2 O)                                                                      H, 7.99 (8.07)                                                                             1572, 1480, 1455                                                                       J=7Hz, 4H); 2.329(m, 3H); 2.33-2.60(m,                                         6H); 2.712(t,                                     needleshaped                                                                            N, 4.69 (4.87)                                                                             1375    J=5Hz, 2H); 3.161(q, J=3Hz, 2H);                                               6.021(quint, J=2Hz, 1H);                          crystals                     7.116, 7.283(ABq, J=9Hz, 4H)                 I a-25                                                                              (maleate)                                                                               C.sub.24 H.sub.39 N.sub.2 O.sub.2.C.sub.4 H.sub.4 O.sub.4                                  (Nujol) (CD.sub.3 OD)                                     148.0˜150.0                                                                       C, 72.65 (72.70)                                                                           2720, 2575(sh),                                                                        1.80-2.01(m, 4H); 2.331(s, 3H);                                                2.48-2.63(m, 4H);                                 (iPrOH--Et.sub.2 O)                                                                     H, 7.36 (7.41)                                                                             2490(sh), 2330,                                                                        2.712(t, J=7Hz, 2H); 2.747(t, J=7Hz,                                           2H); 3.162(q,                                              N, 6.11 (6.06)                                                                             1708, 1652, 1600                                                                       J=3Hz, 2H); 3.283(t, J=6Hz, 2H);                                               3.329(t, J=7Hz, 2H);                                                   1571, 1502, 1459                                                                       6.026(quint, J=2Hz, 1H); 6.50-6.64(m,                                          2H); 6.91-7.32(m, 6H)                        I a-26                                                                              (maleate)                                                                               C.sub.24 H.sub.30 N.sub.2 O.sub.2.C.sub.4                                                  (Nujol) O.sub.4                                                                        (CDCl.sub.3)                                      191.0˜192.0                                                                       C, 66.48 (66.42)                                                                           3030, 2720, 2278                                                                       1.322(s, 9H); 1.76-1.94(m, 8H);                                                2.262(t-d, J.sub.1 =14Hz,                         (MeOH--H.sub.2 O)                                                                       H, 6.61 (6.62)                                                                             1711, 1623, 1572                                                                       J.sub.2 =4Hz, 2H); 2.50-2.65(m, 4H);                                           2.951(d, J=11Hz, 2H);                             needleshaped                                                                            N, 4.92 (4.84)                                                                             1532, 1513(sh),                                                                        3.30-3.39(m, 4H); 5.738(brs, 1H);                                              7.378, 7.418(ABq,                                 crystals             1485, 1463, 1435                                                                       J=8Hz, 4H)                                   I a-27                                                                              (maleate)                                                                               C.sub.23 H.sub.23 F.sub.3 N.sub.2 O.C.sub.4 H.sub.4                                        (CHCl.sub.3)                                                                           (CD.sub.3 OD)                                     152.5˜154.0                                                                       C, 62.64 (62.79)                                                                           2700-1750 (br);                                                                        2.236(quint, J=7Hz, 2H); 2.934(brs,                                            2H); 3.334(t, J=7Hz, 2H);                         (MeOH--Et.sub.2 O)                                                                      H, 5.29 (5.27)                                                                             1695, 1663, 1619                                                                       2.369(t, J=5Hz, 2H); 3.808(t, J=7Hz,                                           2H); 4.010(s, 2H); 4.606                          needleshaped                                                                            N, 5.48 (5.42)                                                                             1532, 1463, 1412                                                                       (s, 2H); 6.230(brs, 2H); 6.298(brs,                                            1H); 7.51-7.81(m, 9H)                             crystals F, 11.00 (11.03)                                                                           1378, 1358                                           I a-28                                                                              (maleate)                                                                               C.sub.19 H.sub.27 N.sub.2 F.sub.3.C.sub.4 H.sub.4 O.sub.4                                  (Nujol) (CDCl.sub.3)                                      182.5˜184.0                                                                       --          3483, 2723, 2679                                                                       0.952(d, J=7Hz, 6H); 2.093(quint.                                              J=7Hz, 3H); 2.636(brs,                            (MeOH--Et.sub.2 O)   2587, 2415, 1703                                                                       2H); 2.727(d, J=7Hz, 2H); 2.771(t,                                             J=6Hz, 2H);                                       needleshaped         1618, 1579, 1478                                                                       2.898(t, J=6Hz, 2H); 3.149(t, J=6Hz,                                           2H); 3.29-3.33(m, 2H);                            crystals             1460, 1412, 1382                                                                       6.184(quint. J=2Hz, 1H); 7.474,                                                7.587(ABq, J=8Hz, 4H)                        I a-29                                                                              (maleate)                                                                               C.sub.27 H.sub.36 N.sub.2.2C.sub.4 H.sub.4 O.sub.4.                                        (Nujol) (CD.sub.3 OD)                                     183.5˜185.0                                                                       1/10H.sub.2 O                                                                              2340, 1708, 1619                                                                       1.330(s, 9H); 2.424(brs, 2H);                                                  2.867(brs, 2H); 3.204(brs, 2H);                   (CHCl.sub.3 --MeOH)                                                                     C, 67.29 (67.59)                                                                           1568, 1528(sh),                                                                        3.370(brs, 4H); 3.544(brs, 4H);                                                3.948(s, 2H); 4.403(s, 2H);                       needleshaped                                                                            H, 7.08 (7.16)                                                                             1485, 1461                                                                             6.060(s, 1H); 6.252(s, 4H);                                                    7.15-7.44(m, 8H)                                  crystals N, 4.56 (4.50)                                                   __________________________________________________________________________      .sup.*1 : a solvent for recrystallization                                

EXAMPLE 30 1-[(3-methylamino)propyl]-4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridine (I a-30) ##STR31##

(1) A solution of 3.60 g of the compound (II-6) and 2.80 g of 1-ethoxycarbonylamino-3-chloropropane in 30 ml of DMF is reacted in the presence of 4.26 g of K₂ CO₃ and 3.46 g of NaI at 105°-110° C. for 6 hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over MgSO₄ and evaporated under reduced pressure. The residue is subjected to column chromatography with silica gel, eluting with methylene chlorde/methanol (10/1-5/1 v/v) to give 4.60 g (Yield: 82.0%) of the compound (IV-6) as crystals. Recrystallization from methylene chloride-ether gives colorless needles. mp. 111.5°-113.0° C.

Anal Calcd. (%) for C₂₁ H₃₄ N₂ O₃. 1/5H₂ O: : C, 68.92; H, 9.37; N, 7.78. Found: C, 68.89; H, 9.47; N, 7.65.

IR (Nujol): 3320, 1715, 1700, 1535

NMR (CDCl₃) δ: 1.242 (t, J=7 Hz, 3H); 1.320 (s, 9H); 1.66-1.84 (m, 4H); 2.210 (td, J₁ =13 Hz, J₂ =4 Hz, 2H) 2.45-2.60 (m, 4H); 2.877 (d, J=12 Hz, 2H); 3.286 (q, J=6 Hz, 2H); 4.103 (q, J=7 Hz, 2H); 5.929 (brs, 1H); 7.376,7.443 (ABq, J=8 Hz, 4H)

(2) A solution of 4.30 g of the compound (IV-6) obtained above in 35 ml of trifluoroacetic acid is refluxed for 5 hours and treated in the same manner as Example 7(2) to prepare 4.05 g (Yield: 99.0%) of the compound (V -4) as an oil.

(3) To a suspension of 146 mg of lithium aluminium hydride in 15 ml of dry ether is added dropwise a solution of 530 mg of the compound (V-4) in 15 ml of THF under stirring. After reflux for 8 hours, the excess reagents are decomposed by careful addition of aq. NaOH and filtered off. The resulting organic layer is dried and evaporated under reduced pressure to prepare 420 mg (Yield: 95.2%) of the compound (I a-30) as an oil.

IR (CHCl₃): 3290, 1602, 1510, 1470, 1445

NMR (CDCl₃): 1.321 (s, 9H); 1.780 (quint, J=7 Hz, 2H); 2.444 (s, 3H); 2.48-2.62 (m, 2H); 2.532 (t, J=7 Hz, 2H); 2.672 (t, J=7 Hz, 2H); 3.152 (q, J=3 Hz, 2H); 6.039 (quint, J=2 Hz, 1H); 7.333 (s, 4H)

EXAMPLE 31 1-[N-methyl-N-[3-{4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propylcarbamoyl]]-2-oxopyrrolidine (I a-31) ##STR32##

A mixture of 400 mg of the compound (I a-30) obtained in Example 30 and 280 mg of 1-phenoxycarbonyl-2-oxopyrrolidine is heated at 115° C. for 2 hours. The reaction mixture is subjected to column chromatography with silica gel; eluting with toluene/ethyl acetate (1/1)-methylene chloride/methanol (20/1) to prepare 370 mg (Yield: 68.5%) of the compound (I a-31) as an oil. The tosylate is recrystallized from ethyl acetate/methanol to prepare needles. mp. 128.0°-134.0° C.

Anal Calcd. (%) for C₂₄ H₃₅ N₃ O₂. C₇ H₈ O₃ S. H₂ O: C, 63.51; H, 7.56; N, 7.16; S, 5.37. Found: C, 63.35; H, 7.72; N, 7.15; S, 5.45.

IR (Nujol) cm⁻¹ : 3570, 3500, 2740, 2630, 1720, 1690, 1675(sh), 1663, 1475, 1120, 1033

NMR (CDCl₃) δ: 1.314 (s, 9H); 1.895 (quint, J=7 Hz, 2H); 2.071 (quint, J=7 Hz, 2H); 2.454 (t, J=8 Hz, 2H); 2.50-2.60 (m, 4H); 2.720 (t, J=5 Hz, 2H); 2.995 (s, 3H); 3.174 (q, J=3 Hz, 2H); 3.461 (t, J=7 Hz, 2H); 3.735 (t, J=7 Hz, 2H); 6.024 (quint, J=2 Hz, 1H); 7.244, 7.348 (ABq, J=8 Hz, 4H)

EXAMPLE 32 1-[(3-methylamino)propyl]-4-(4-phenylphenyl-1,2,5,6-tetrahydropyridine (I a-32) ##STR33##

(1) A solution of 3.20 g of the compound (II-5) and 2.30 g of 1-ethoxycarbonylamino-3-chloropropane in 30 ml of DMF is reacted in the presence of 3.48 g of K₂ CO₃ and 2.83 g of NaI at 105° C. for 41 hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over MgSO₄ and evaporated under reduced pressure. The residue is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol (10/1-5/1v/v). The resulting purified substance is recrystallized from methylene chloride to prepare 2.46 g (Yield: 51.0%) of the compound (IV-7). mp. 138.0°-139.0° C.

Anal Calcd. (%) for C₂₃ H₃₀ N₂ O₃ : C, 72.22; H, 7.84; N, 7.30. Found: C, 72.22; H, 7.91; N, 7.32.

IR (CHCl₃) cm⁻¹ : 3600, 3450, 1705, 1602, 1512, 1490

NMR (CDCl₃) δ: 1.240 (t, J=7 Hz, 3H); 1.60-1.80 (m, 4H); 1.830 (s, 1H); 2.195 (t-d, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.480 (d-d, J₁ =14 Hz, J₂ =2 Hz, 2H); 2.524 (t, J=7 Hz, 2H); 2.850 (d, J=14 Hz, 2H); 3.280(q, J=6 Hz, 2H); 4.101 (q, J=7 Hz, 2H); 6.962 (brs, 1H); 7.25-7.70 (m, 9H) 9H)

(2) A solution of 2.29 g of the compound (IV-7) in 25 ml of trifluoroacetic acid is refluxed for 9.5 hours and treated in the same manner as Example 7 (2) to prepare 2.08 g (Yield: 95.3%) of the compound (V-5). mp. 135.0°-138.0° C.

(3) To a solution of 1.80 g of the compound (V-5) in 26 ml of THF is added dropwise 375 mg of lithium alminium hydride. After reflux for 8 hours, the reaction mixture is treated in the same manner as Example 29 (3) to prepare (I a-32) as an oil.

EXAMPLE 33

1-[3-{4-(4-phenylphenl)-1,2,5,6-tetrahydropyridin-1-yl} propylmethylcarbamoyl]-2-oxopyrrolidine (I a-33) ##STR34##

To the compound (I a-32) obtained Example 32 is added dropwise 810 mg of 1-phenoxycarbonyl-2-oxopyrrolidine, and the mixture is heated at 115°-120° C. for 5 hours. The reaction mixture is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol (20/1 v/v) to prepare 650 mg (Yield: 31.5%) of the compound (I a-33). The oxalate is recrystallized from i-PrOH to give needles. mp. 186.0°-187.0° C. (dec.)

Anal Calcd. (%) for C₂₆ H₃₁ N₃ O₂.C₂ H₂ O₄.1/2H₂ O: C, 64.71; H, 6.52; N,7.97. Found: C, 65.10; H, 6.63; N,8.13.

IR (Nujol): 3500(br), 2720, 2600, 1720, 1665, 1485, 1455, 1405, 1405, 1375

NMR (CDCl₃) δ: 1.900 (quint, J=7 Hz, 2H); 2.107 (quint, J=7 Hz, 2H); 2.455 (t, J=8 Hz, 2H); 2.55-2.64 (m, 4H); 2.741 (t, J=5 Hz, 2H); 3.002 (s, 3H); 3.198 (q, J=3 Hz, 2H); 3.469 (t, J=7 Hz, 2H); 3.737 (t, J=7 Hz, 2H); 6.124 (quint, J=2 Hz, 1H) 7.3-7.6 (m, 9H)

EXAMPLE 34 1-[3-(N-methyl-N-isobutyl)aminopropyl]-4-(4-trifluoromethylphenyl)-1,2,5,6-tetrahydropyridine (I a-34) ##STR35##

A mixture of 342 mg of the compound (I a-23), 1 ml of formaldehyde, and 1 ml of formic acid is stirred at 70° C. for 3 hours and 40 minutes. The reaction mixture is concentrated, and the residue is poured into aq.NaHCO₃. The solution is extracted with methylene chloride-methanol, and the organic layer is dried over MgSO₄ and evaporated under reduced pressure. The resulting oily substance is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol (19/1-5/1 v/v) to prepare 252 mg of the objective compound (I a-34). The maleate is recrystallized from ethnol-ether to prepare 325 mg (Yield: 55.2%) of colorless needles. mp. 182.0°-183.5° C.

Anal Calcd. (%) for C₂₀ H₂₉ N₂ F₃.2C₄ H₄ O₄ : C, 57.16; H, 6.32; N, 4.82; F, 9.46. Found: C, 57.33; H, 6.36; N, 4.78; F, 9.72.

IR (Nujol): 2360, 1708, 1621, 1570, 1533, 1481, 1460, 1447(sh), 1377, 1359

NMR (CDCl₃): 0.938 (d, J=7 Hz, 6H); 1.826 (quint, J=7 Hz, 3H); 2.212 (d, J=7 Hz, 2H); 2.309 (s, 3H); 2.513 (t, J=7 Hz, 2H); 2.548 (t, J=7 Hz, 2H); 2.58, 2.63 (m, 2H); 2.747 (t, J=5 Hz, 2H); 3.208 (q, J=3 Hz, 2H); 6.161 (quint, J=2 Hz, 1H); 7.474, 7.567 (ABq, J=8 Hz, 4H)

EXAMPLE 35

4-[3-{4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propyl]morpholine (I a-35) ##STR36##

(1) A mixture of 1.09 g of the compound (IV-2) obtained in Example 18 and 1.4 g of morpholine is refluxed for 4 hours. After removal of the excess reagent under reduced pressure, the residue is poured into aq.Na₂ SO₄ and evaporated. The residue is purified by column chromatography with silica gel, eluting with mthylene chloride/methanol (20/1 v/v). The hydrochloride of the compound (III-19) is crystallized from methylene chloride-ether to prepare 850 mg (Yield: 66.3%) of needles. mp. 242° C. (dec.)

NMR (CDCl₃.CD₃ OD=10/1): 1.307 (s, 9H); 2.10-2.22 (m, 2H); 2.48-2.55 (m, 4H); 2.760 (td, J₁ =15 Hz, J₂ =4 Hz, 2H); 3.06-3.15 (m, 4H); 3.25-3.50 (m, 4H); 3.731 (t, J=5 Hz, 4H); 7.387, 7.454 (ABq, J=9 Hz, 4H)

(2) A solution of 880 mg of the compound (III-19) in 10 ml of trifluoroacetic acid is refluxed for 8 hours and evaporated under reduced pressure. The residue is poured into aq. sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer is washed with saline, dried over Na₂ SO₄ and evaporated. The residue is purified by column chromatography followed by crystallization as the maleate. Recrystallization from methanol gives 760 mg (Yield: 97.5%) of redish needles. mp. 213.0°-214.5° C. (dec.)

Anal Calcd. (%) for C₂₂ H₃₄ N₂ O.2C₄ H₄ O₄ : C, 62.63; H, 7.35; N, 4.93. Found: C, 62.70; H, 7.37; N, 4.87.

IR (Nujol): 2300 (br); 1717, 1622, 1675, 1535, 1500, 1465, 1458, 1450(sh)

NMR (CDCl₃): 1.314 (s, 9H); 1.783 (quint, J=7 Hz, 2H); 2.36, 2.63 (m, 8H); 2.709 (t, J=5 Hz, 2H); 3.164 (q, J=3 Hz, 2H); 3.725 (t, J=5 Hz, 2H); 6.031 (quint, J=1 Hz, 1H); 7.330 (s, 4H)

EXAMPLE 36-71

The reaction is performed in the same manner as Example 1 to prepare the compound (I a). The reaction conditions are shown in Table 7 and 8. Further the physical constants of the compound (I a) obtained in Example 36-71 are shown in Table 9.

    TABLE 7       (Step 1)  starting     reaction  g (%)   Exam. material  DMF K.sub.2      CO.sub.3 NaI condition (1) purification Compd. m.p.  No. X= R(CH.sub.2)nY      (VI) (ml) (g) (g) (°C. hr.) condition No. (°C.) IR      (cm.sup.-1)       ##STR37##                  36 Me (p)2.50 g(II-8)      ##STR38##       35 4.53 2.95 105-1107 hr. CH.sub.2 Cl.sub.2       /MeOH =10/1 3.46(76.4)(III-20) 116.0˜117.0 (CHCl.sub.3)3600,      3320, 1713,1688 (sh), 1680,1545, 1490       37 Me (p)2.34 g(II-8)      ##STR39##       25 4.21 2.74 1056 hr. toluene/ethyl acetone =20/1-10/1 3.07(70.0)(III-21      ) 143.5˜144.5 (CHCl.sub.3)3600, 3320, 1715,1618, 1550-1520  38 Me      (m) (VI-1) 2.35 g 30 3.18 2.59 105-110 CH.sub.2 Cl.sub.2 /MeOH = 1.70 --      (CHCl.sub.3)  1.85 g     8 hr. 10/1 (49.0)  3600, 3320, 1715,  (II-9)         (III-22)  1680, 1608, 1545,           1490, 1470 39 Me (o) (VI-1)      2.68 g 35 4.53 2.95 105-110 CH.sub. 2 Cl.sub.2       /MeOH = 3.18 -- (CHCl.sub.3)  2.50 g     7 hr. 10/1 (67.5)  3600, 3320,      1712,  (II-10)       (III-23)  1680, 1600, 1545,           1489, 1470,      1460 40 3,4- (VI-1) 2.09 g 35 2.82 2.29 105 CH.sub.2 Cl.sub.2 /MeOH =      2.56 -- --  di-Me     7 hr. 10/1 (67.2)  2.10 g       (III-24)  (II-11)      41 3,5- (VI-1) 2.81 g 35 3.79 3.08 105° C. CH.sub.2 Cl.sub.2      /MeOH = 3.81 -- (CHCl.sub.3)  di-Me     6 hr. 10/1 (74.4)  3595, 3310,      1715,  2.82 g       (III-25)  1680, 1590, 1565,  (II-12)         1545,      1489, 1470           1460, 42 Cl (m) (VI-1) 2.49 g 30 4.18 2.72 105-110.d      egree. C. CH.sub.2 Cl.sub.2 /MeOH = 3.78 90.5˜ (CHCl.sub.3)  2.70      g     7 hr. 20/1-10/1 (81.8) 91.5 3600, 3220, 1713,  (II-13)      (III-26)  1658, 1595, 1545,           1490, 1470, 1460 43 Cl (m) (VI-7)      2.31 g 30 4.18 2.72 105-110° C. CH.sub.2 Cl.sub.2 /MeOH = 3.30      94.0˜ (Nujol)  2.70 g     7 hr. 10/1 (74.3) 98.0 3280, 2720-2520,      (II-13)       (III-27)  1713, 1685, 1600,           (sh), 1588, 1560 44      Cl (o) (VI-1) 2.42 g 30 4.08 2.65 105-110 ethyl acetate/ 2.10 --      (CHCl.sub.3)  2.50 g     6 hr. toluene = 1/1 (46.7)  3580, 3320, 1715,      (II-14)      CH.sub.2 Cl.sub.2 /MeOH = (III-28)  1680, 1547        15/1      45 Cl (o) (VI-7) 1.28 g 20 2.32 1.51 105-110 CH.sub.2 Cl.sub.2 /MeOH =      0.840 -- (CHCl.sub.3)  1.45 g     6 hr. 15/1 (34.1)  3580, 3220, 1715,      (II-14)       (III-29)  1680, 1545(sh),           1540(sh), 1525 46      3,5-diCl (VI-1) 3.0 g 35 4.04 3.28 105° C. CH.sub.2 Cl.sub.2      /MeOH = 5.25 138.0˜ (CHCl.sub.3)  3.86 g     7.0 hr. 10/1 (86.8)      140.0 3595, 3310, 1715,  (II-15)       (III-30)  1680, 1590, 1565,          1545 47 Br (p) (VI-1) 1.96 g 25 2.64 2.15 105° C. CH.sub.2      Cl.sub.2 /MeOH = 3.16 -- (CHCl.sub.3)  2.57 g     8 hr. 10/1 (77.9)      3590, 3310, 1713,  (II-16)       (III-31)  1680, 1545, 1489,      1460 48 F (p) (VI-1) 4.20 g 50 7.08 4.61 105-110° C. CH.sub.2      Cl.sub.2 /MeOH = 4.96 102.5˜ (CHCl.sub.3)  4.00 g     6.0 hr.      15/1-8/1 (66.5) 104.0 3600, 3320, 1713,  (II-17)       (III-32)  1680,      1545, 1510,           1489 49 F (p) (VI-7) 2.25 g 25 4.08 2.65 105.degree      . C. CH.sub.2 Cl.sub.2 /MeOH = 2.78 118.0˜ (CHCl.sub.3)  2.30 g       6 hr. 10/1 (67.4) 119.0 3600, 3320, 1713,  (II-17)       (III-33)      1680, 1605, 1545,           1510, 1489 50 CF.sub.3 (m) (VI-1) 2.56 g 50      3.46 2.81 105-110° C. CH.sub.2 Cl.sub.2 /MeOH = 5.20 238.5˜      (Nujol)  Cl (p)     9 hr. 20/1-10/1 (92.9) 240.5 3350, 2650, 2525,  3.50      g       (III-34)  2450, 1720, 1677,  (II-18)         1557 51 CF.sub.3      (m) (VI-7) 2.38 g 50 3.46 2.81 105-110 CH.sub.2 Cl.sub.2 /MeOH = 4.75      255.0˜ (Nujol)  Cl (p)     15 hr. 20/1-10/1 (87.6) 257.0 3400,      3260, 2640,  3.50 g       (III-35)  2500, 2430, 1713,  (II-18)      1672, 1547       ##STR40##        52 2.80 g (VI-1) 2.64 g 36 4.46 2.90 105-110 CH.sub.2 Cl.sub.2 /MeOH = 3      .55 122.0˜ (CHCl.sub.3)  (II-19)     8 days 10/1 (71.3) 123.0      3590, 3320, 1713,  *1       (III-36)  1680, 1544, 1490,           1470,      1460(sh),           1450 53 2.10 g (VI-1) 1.70 g 30 1.73 2.50 105      CH.sub.2 Cl.sub.2 /MeOH = 3.00 -- (CHCl.sub.3)  (II-20)     7 days 10/1      ##STR41##      ##STR42##     54 Cl (p) (VI-5) 1.03 g 10 1.63 1.06 90 CH.sub.2 Cl.sub.2 /MeOH = 1.37      111.5- (CHCl.sub.3)  1.00 g     12 hr. 20/1-10/1 (74.0) 112.0 3600,      3280, 1702,  (II-21)       (III-38)  1698, 1530, 1645,           1495,      1480, 1463       55 Cl (p)2.0 g(II-21)       25 3.26 2.12 90-9510 hr. CH.sub.2 Cl.sub.2       /MeOH =10/1 1.75(48.7)(III-39) 128.0-129.0 (CHCl.sub.3)3600, 3280,      1      1525,492, 1480, 1460       56 t-Bu (p)1.00 g(II-6)      ##STR43##       10  K.sub.2 CO.sub.3 1.184 NaI0.96 100° C.3 hr. CH.sub.2      Cl.sub.2 /MeOH/NH.sub.4       OH =64/8/1 1.13(71.0)(III-40) -- (CHCl.sub.3)3590, 2498, 1510,1470,      1455, 1399  57 Me (p) (VI-9) 1.10 g 10 K.sub.2 CO.sub.3 NaI 100°      C. CH.sub.2 Cl.sub.2 /MeOH/ 1.445 -- (CHCl.sub.3)  1.00 g   1.45 1.18      2.5 hr. NH.sub.4 OH = (83.6)  3580, 2498, 1510,  (II-8)      64/8/1      (III-41)  1463, 1450, 1375       58 tBu (p)0.81 g(II-6)      ##STR44##       12 K.sub.2 CO.sub.3 0.96 NaI0.78 100° C.2.7 hr. CH.sub.2      Cl.sub.2 /MeOH/NH.sub.4       OH =64/8/1 1.053(84.6)(III-42) -- (CHCl.sub.3)3580, 2498, 1510,1463,      1450, 1375       59  tBu (p)0.727 g(II-6)      ##STR45##       11 K.sub.2 CO.sub.3 0.86 NaI0.70 100°       C.2.5 hr. -- 0.736(62.4)(III-43) -- (CHCl.sub.3)3630, 3590, 3390,2499,      1506, 1467,1440, 1421, 1399  60 Me (p) NO(CH.sub.2).sub.3 Cl (VI-12) --      Et.sub.3 N 140° C. CH.sub.2 Cl.sub.2 /MeOH = 8.51 g 183.0      (CHCl.sub.3)  10.2 g 5.81 ml  11.16 ml 4.0 hr. 9/1 (64.0) 185.0 3597,      3220, 1513,  (II-8)      (III-44)  1470, 1452, 1437,          1423, 1397 6      1 Me (p) (VI-3) 964 mg 15 K.sub.2 CO.sub.3 NaI 105° C. CH.sub.2      Cl.sub.2 /MeOH = 0.74 g 170.0˜ (CHCl.sub.3)  0.964 g   1.40 g 1.14      g 5.75 hr. 9/1 (41.7) 172.5 3675, 3599, 3465,  (II-8)      CH.sub.2      Cl.sub.2 /MeOH/ (III-45)  3285, 2465, 1631,        NH.sub.4 OH = 64/8/1       1521, 1488, 1478,           1462, 1457(sh),           1439(sh), 1402 62      Ph (p) (VI-3) 0.70 g 11 K.sub.2 CO.sub.3 NaI 105° C. CH.sub.2      Cl.sub.2 /MeOH = 616 mg 225.0˜ (Nujol)  0.93 g   1.02 g 0.93 g      5.75 hr. 10/1 (41.0) 228.0 3300, 3055, 3030,  (II-5)      CH.sub.2      Cl.sub.2 /MeOH/ (III-46) (dec.) 2810, 2770, 2670,        NH.sub.4 OH =      1606, 1528, 1487,        128/16/1 = 32/6/1   1471, 1456, 1448  63      CF.sub.3 (p)1.50 g(II-2)       ##STR46##       20 K.sub.2 CO.sub.3 1.69 g NaI1.38 mg 105° C.8.0 hr. CH.sub.2      Cl.sub.2       MeOH =20/1-10/1 0.56 g(19.1)(III-47) 142.5-144.0 (CHCl.sub.3)3690,      3600, 1637(sh)1632, 1587, 1552,1510(sh), 1495, 1440  64 Me (p)1.44      g(II-8)       ##STR47##       CH.sub.2 Cl.sub.2 20 Et.sub.2 N1.16 ml roomtemperature92 hr. CH.sub.2      Cl.sub.2 MeOH/NH.sub.4 OH =128/10/1 ˜64/8/1 2.11 g(88.4)(III-48)      -- --        Exam.   DMF K.sub.2 CO.sub.3 NaI reaction purification g (%)  No. (II)      R(CH.sub.2)nY (VI) ml g g condition condition (1) (III) m.p. (°C.)        65 (II-6) (VI-7) 3.00 g 45 4.35 3.54 105° C., 8 hr. CH.sub.2      Cl.sub.2 /MeOH = 4.90 (73.5) 219.0˜  3.67 g      29/1˜9/1      (III-49) 222.0 66 (II-1) (VI-7) 3.07 g 45 4.04 3.28 105° C., 9      hr. CH.sub.2 Cl.sub.2 /MeOH = 5.57 (95.0) 232.0˜  3.60 g      10/1      (III-50) 239.0 67 (II-2) (VI-7) 3.34 g 45 4.63 3.93 105° C., 9      hr. CH.sub.2 Cl.sub.2 /MeOH = 6.11 (87.4) 266.0˜  4.70 g      15/1˜10/1 (III-51) 268.0 68 (II-16) (VI-7) 2.50 g 35 3.62 2.95      105° C., 12 hr. CH.sub.2 Cl.sub.2       /MeOH = 4.50 (83.7) 230.0˜  3.36 g      10/1 (III-52) 232.0 69      (II-5) (VI-7) 3.00 g 45 4.35 3.54 105° C., 8 hr. CH.sub.2      Cl.sub.2 /MeOH = 5.61 (80.3) 233.0˜  3.99 g      39/1˜19/1      (III-53) 238.0 70 (II-3) (VI-7) 3.00 g 45 4.35 3.54 105° C., 6.5      hr. CH.sub.2 Cl.sub.2 /MeOH = 5.34 (82.7) 203.0˜  3.45 g      39/1˜9/1 (III-54) 207.5 71 (II-22)* (VI-1) 2.23 g 30 3.01 2.44      105° C., 8.5 hr. CH.sub.2 Cl.sub.2       /MeOH = 1.35 (30.5) 95.0˜  2.60 g      10/1˜5/1 (III-55)      96.5      ##STR48##

                                      TABLE 8                                      __________________________________________________________________________     (Step 2)                                                                       (III)                    purification                                                                               Product                                   (g)  acid  solvent (ml)                                                                          reflux time                                                                           condition (2)                                                                              g (%)                                     __________________________________________________________________________     (III-20)                                                                            TsOH.H.sub.2 O                                                                       toluene (60)                                                                          13 hr. ethyl acetate                                                                              I a-36                                    2.53 g                                                                              (2.68 g)                                                                             CH.sub.2 Cl.sub.2 (20)                                                                       CH.sub.2 Cl.sub.2 /MeOH = 10/1                                                             2.17 g                                                                         (90.3)                                    (III-21)                                                                            TsOH.H.sub.2 O                                                                       toluene (300)                                                                         30 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                             I a-37                                    2.66 g                                                                              (2.93 g)                                                                             CH.sub.2 Cl.sub.2 (50)    2.27 g                                                                         (90.0)                                    (III-22)                                                                            TsOH.H.sub.2 O                                                                       toluene (300)                                                                         48 hr. ethyl acetate                                                                              I a-38                                    3.30 g                                                                              (3.49 g)            CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                             2.50 g                                                                         (80.0)                                    (III-23)                                                                            TsOH.H.sub.2 O                                                                       toluene (250)                                                                         69 hr. toluene/ethyl                                                                              I a-39                                    3.18 g                                                                              (4.21 g)                                                                             CH.sub.2 Cl.sub.2 (60)                                                                       acetate = 1/1                                                                              2.96 g                                                             CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                             (Quantitative)                            (III-24)                                                                            CF.sub.3 COOH                                                                        --     8 hr.  toluene/ethyl                                                                              I a-40                                    2.56 g                                                                              (27 ml)             acetate = 30/1                                                                             2.40 g                                                                         (98.0)                                    (III-25)                                                                            CF.sub.3 COOH                                                                        --     8.5 hr.                                                                               CH.sub.2 Cl.sub.2 /MeOH = 30/1                                                             3.50 g                                    3.80 g                                                                              (26 ml)                         3.50 g                                                                         (96.8)                                    (III-26)                                                                            TsOH.H.sub.2 O                                                                       toluene (250)                                                                         27 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                             I a-42                                    3.16 g                                                                              (3.16 g)                                                                             CH.sub.2 Cl.sub.2 (70)    2.20 g                                                                         (73.1)                                    (III-27)                                                                            TsOH.H.sub.2 O                                                                       toluene (200)                                                                         48 hr. toluene/ethyl                                                                              I a-43                                    2.45 g                                                                              (2.55 g)                                                                             CH.sub.2 Cl.sub.2 (50)                                                                       acetate = 1/1                                                                              1.87 g                                                             CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                             (80.2)                                    (III-28)                                                                            TsOH.H.sub.2 O                                                                       toluene (100)                                                                         29 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                             I a-44                                    2.10 g                                                                              (1.60 g)            ethyl acetate                                                                              1.480 g                                                                        (73.8)                                    (III-29)                                                                            TsOH.H.sub.2 O                                                                       toluene (60)                                                                          31 hr. CH.sub.2 Cl.sub.2 /MeOH = 15/1                                                             I a-45                                    0.84 g                                                                              (0.52 g)                        0.80 g                                                                         (Quantitative)                            (III-30)                                                                            CF.sub.3 COOH                                                                        --     39 hr. CH.sub.2 Cl.sub.2 /MeOH = 30/1                                                             I a-46                                    2.10 g                                                                              (10 ml)                         1.34 g                                                                         (70.2)                                    (III-31)                                                                            CF.sub.3 COOH                                                                        --     8 hr.  CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                             I a-47                                    3.51 g                                                                              (36 ml)                         2.80 g                                                                         (92.9)                                    (III-32)                                                                            TsOH.H.sub.2 O                                                                       toluene (250)                                                                         26.5 hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                             I a-48                                    4.14 g                                                                              (3.25 g)                        3.16 g                                                                         (80.3)                                    (III-33)                                                                            TsOH.H.sub.2 O                                                                       toluene (160)                                                                         16 hr. CH.sub.2 Cl.sub.2 /MeOH = 15/1                                                             I a-49                                    1.93 g                                                                              (2.10 g)                                                                             CH.sub.2 Cl.sub.2 (60)    1.50 g                                                                         (81.9)                                    (III-34)                                                                            CF.sub.3 COOH                                                                        --     25 hr. CH.sub.2 Cl.sub.2 /MeOH =                                                                  I a-50                                    3.10 g                                                                              (35 ml)             30/1-20/1   2.80 g                                                                         (94.1)                                    (III-35)                                                                            CF.sub.3 COOH                                                                        --     19.5 hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH =                                                                  I a-51                                    2.70 g                                                                              (35 ml)             50/1-20/1   2.40 g                                                                         (92.7)                                    (III-36)                                                                            TsOH.H.sub.2 O                                                                       toluene (280)                                                                         26 hr. toluene = ethyl                                                                            I a-52                                    4.09 g                                                                              (4.03 g)                                                                             CH.sub.2 Cl.sub.2 (70)                                                                       acetate = 3/1                                                                              3.76 g                                                             CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                             (96.4)                                    (III-37)                                                                            CF.sub.3 COOH                                                                        --     8 hr.  CH.sub.2 Cl.sub.2 /MeOH = 25/1                                                             I a-53                                    3.00 g                                                                              (30 ml)                         2.57 g                                                                         (89.5)                                    (III-38)                                                                            TsOH.H.sub.2 O                                                                       benzene (150)                                                                         23 hr. CH.sub.2 Cl.sub.2 /MeOH =                                                                  I a-54                                    2.86 g                                                                              (2.76 g)                                                                             CH.sub.2 Cl.sub.2 (50)                                                                       10/1-20/1   1.48 g                                                                         (48.7)                                    (III-39)                                                                            TsOH.H.sub.2 O                                                                       benzene (150)                                                                         25 hr. toluene/ethyl                                                                              I a-55                                    1.00 g                                                                              (1.00 g)                                                                             toluene (100) acetate = 1/1                                                                              0.93 g                                                             CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                             (97.7)                                    (III-40)                                                                            CF.sub.3 COOH                                                                               1.0 hr.                                                                               CH.sub.2 Cl.sub.2 /MeOH/                                                                   I a-56                                    1.134 g                                                                             (10 ml)             NH.sub.4 OH = 64/8/1                                                                       1.416 g                                                                        (79.3)                                    (III-41)                                                                            CF.sub.3 COOH                                                                               1.5 hr.                                                                               CH.sub.2 Cl.sub.2 /MeOH/                                                                   I a-57*                                   1.445 g                                                                             (10 ml)             NH.sub.4 OH = 64/8/1                                                                       1.787 g                                                                        (75.1)                                    (III-42)                                                                            CF.sub.3 COOH                                                                               50 min.                                                                               CH.sub.2 Cl.sub.2 /MeOH/                                                                   I a-58*                                   1.002 g                                                                             (10 ml)             NH.sub.4 OH = 64/8/1                                                                       1.117 g                                                                        (69.8)                                    (III-43)                                                                            CF.sub.3 COOH                                                                               1 hr.  CH.sub.2 Cl.sub.2 /MeOH/                                                                   I a-59*                                   0.722 g                                                                             (6 ml)              NH.sub.4 OH = 128/12/1-                                                                    0.881 g                                                            64/8/1      (64.6)                                    (III-44)                                                                            CF.sub.3 COOH                                                                               3.17 hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH/                                                                   I a-60                                    12.82 g                                                                             (38.3 ml)           NH.sub.4 OH = 128/16/1-                                                                    7.719 g                                                            32/6/1      (64.9)                                    (III-45)                                                                            CF.sub.3 COOH                                                                               1.5 hr.                                                                               CH.sub.2 Cl.sub.2 /MeOH/                                                                   I a-61*                                   721 mg                                                                              (10 ml)             NH.sub.4 OH = 128/16/1                                                                     664 mg                                                                         (73.1)                                    (III-46)                                                                            CF.sub.3 COOH                                                                               1 hr.  CH.sub.2 Cl.sub.2 /MeOH =                                                                  I a-62*                                   766 mg                                                                              (10 ml)             19/1˜9/1                                                                             572 mg                                                                         (60.5)                                    (III-47)                                                                            CF.sub.3 COOH                                                                               48 hr. CH.sub.2 Cl.sub.2 /MeOH =                                                                  I a-63                                    540 mg                                                                              (8 ml)              30/1˜10/1                                                                            529 mg                                                                         (69.2)                                    (III-48)                                                                            CF.sub.3 COOH                                                                               1.25 hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH = 19/1                                                             I a-64                                    2.105 g                                                                             (5 ml)       room               1.693 g                                                     temperature        (85.3)                                    (III-49)                                                                            CF.sub.3 COOH                                                                               50 min.                                                                               CH.sub.2 Cl.sub.2 /MeOH = 49/1                                                             I a-65                                    2.87 g                                                                              (35 ml)                         2.61 g                                                                         (86.7)                                    (III-50)                                                                            CF.sub.3 COOH                                                                               8 hr.  CH.sub.2 Cl.sub.2 /MeOH =                                                                  I a-66                                    2.85 g                                                                              (30 ml)             20/1-10/1   2.70 g                                                                         (98.6)                                    (III-51)                                                                            CF.sub.3 COOH                                                                               3 days CH.sub.2 Cl.sub.2 /MeOH =                                                                  I a-67                                    3.85 g                                                                              (50 ml)             15/1-10/1   3.53 g                                                                         (96.0)                                    (III-52)                                                                            CF.sub.3 COOH                                                                               7 hr.  CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                             I a-68                                    1.75 g                                                                              (25 ml)                         1.54 g                                                                         (92.0)                                    (III-53)                                                                            CF.sub.3 COOH                                                                               50 min.                                                                               CH.sub.2 Cl.sub.2 /MeOH = 49/1                                                             I a-69                                    2.98 g                                                                              (34 ml)                         2.71 g                                                                         (87.1)                                    (III-54)                                                                            CF.sub.3 COOH                                                                               50 min.                                                                               toluene/acetone =                                                                          I a-70                                    2.62 g                                                                              (33 ml)             9/1-3/1     2.41 g                                                                         (87.5)                                    (III-55)                                                                            CF.sub.3 COOH                                                                               2.5 hr.                                                                               CH.sub.2 Cl.sub.2 /MeOH =                                                                  I a-71                                    1.58 g                                                                              (20 ml)             15/1-7/1    1.28 g                                                                         (49.5)                                    __________________________________________________________________________      *: maleate                                                               

    TABLE 9       Compd. m.p. (°C.) Anal. Calcd. (%)   No. (solvent*) Found (%) IR      (cm.sup.-2) NMR (δ)        Ia-36 130.5-132.0 C.sub.19 H.sub.25 N.sub.3 O.sub.2 : (CHCl.sub.3)      (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 --Et.sub.2 O) C, 69.42 (69.70) 3310,      1713, 1680 2.020(quint, J=8Hz, 2H); 2.329(s, 3H, J=7Hz, 2H); 2.56-2.59(m,         H, 7.65 (7.70) 1545,1489, 1460 4H); 2.671(t, J=7Hz, 2H); 2.766(t,      J=6Hz, 2H); 3.217(q. J=3Hz,   N, 12.76 (12.83  2H); 3.510(q, J=7Hz, 2H);      3.859(t, J=7Hz, 2H); 6.016(quint, J=3     Hz, 1H); 7.116(d, J=8Hz, 2H);      7.284(d, J=8Hz, 2H); 8.596(br, 1H) Ia-38 161.5-163.0 C.sub.22 H.sub.29      N.sub.3 O.sub.6 : (Nujol) (CDCl.sub.3)  (iPrOH) C, 60.86 (61.24) 3330,      2600, 2500 1.782 (quint, J-7Hz, 2H); 1.969(quint, J=8Hz, 2H); 2.301(s,      3H);  (oxalate) H, 6.79 (6.77) 1717, 1645, 1605 2.44-2.59(m, 6H);      2.658(t, J=6Hz, 2H); 3.111(q, J=3Hz, 2H); 3.3   N, 9.51 (9.74) 1533,      1485, 1460 47(q, J=7Hz, 2H); 3.813(t, J= 7Hz, 2H); 5.999(quint, J=3Hz,      1H);     6.00-7.02(m, 1H); 7.14-7.16(m, 3H); 8.456(brs, 1H) Ia-39      146.0-147.0 C.sub.22 H.sub.29 N.sub.3 O.sub.6 : (Nujol) (CDCl.sub.3)      (iPrOH) C, 61.08 (61.24) 3300, 2600(br). 1.873(quint, J=7Hz, 2H);      2.030(quint, J=8Hz, 2H); 2.297(s, 3H);  (oxalate) H, 6.70 (6.77) 1708,      1683, 1548 2.38-2.48(m, 1H); 2.593(t, J=7Hz, 2H); 2.606(t, J=8Hz, 2H);      2.7   N, 9.71 (9.74) 1490(sh), 1460 46(t, J=6Hz, 2H); 3.184(q, J=3Hz,      2H); 3,402(quint, J=7Hz, 2H);     5.531(quint, J=2Hz, 1H); 7.11-7.17(m,      4H); 8.519(brs, 1H) Ia-40 146.5-147.5 C.sub.25 H.sub.33 N.sub.3 O.sub.6      (Nujol) (CDCl.sub.3)  (iPrOH) C 63.40 (63.68) 3330, 2420-2300, 1.825(quin      t, J=8Hz, 2H); 2.020(quint, J=7Hz, 2H); 2.240(s, 3H);  (maleate) H, 6.99      (7.05) 1700, 1620, 1575 2.254(s, 3H); 2.48-2.56(m, 4H); 2.594(t, J=8Hz,      2H); 2.697(t,   N, 3.87 (8.91) 1530, 1460, 1450 J=5Hz, 2H); 3.147(q,      J=3Hz, 2H); 3.390(q, J=7Hz, 2H); 3.859(t,    (sh) J=7Hz, 2H); 6.002(quint      , J=2Hz, 1H); 7.04-7.15(m, 3H); 8.489     (brs, 1H) Ia-41 159.0-160.0      C.sub.25 H.sub.33 N.sub.3 O.sub.6 (Nujol) (CDCl.sub.3)  (iPrOH) C, 63.71      (63.38) 3290, 2400-2300, 1.821(quint, J=7Hz, 2H); 2.013(quint, J=8Hz,      2H); 2.300(s, 6H);  (maleate) H, 7.05 (7.05) 1720(sh), 1710 2.48-2.55(m,      4H); 2.592(t, J=7Hz, 2H); 2.690(t, J=6Hz, 2H); 3.1   N, 8.86 (8.91)      1685, 1620, 1600 42(q, J=3Hz, 2H); 3.385(q, J=7Hz, 2H); 3.855(d-d,      J.sub.1 =8Hz, J.sub.2 =    (sh), 1577, 1550 7Hz, 2H); 6.014(quint,      J=2Hz, 1H); 6.878(s, 1H); 6.998(s, 2H) Ia-42 155.5-157.0 C.sub.23      H.sub.29 N.sub.3 O.sub.6 Cl (Nujol) (CDCl.sub.3)  (iPrOH) C, 57.74      (57.80) 3310, 2350, 2260 1.825 (quint, J=7Hz, 2H); 2.022(quint, J=8Hz,      2H); 2.49-2.56(m,  (maleate) H, 5.84 (5.90) 1715,1682,1585 4H); 2.538(t,      J=7Hz, 2H); 2.709(t, J=6Hz);3.259(q, J=3Hz, 2H);   N, 8.78 (8.79) 1520,      1485(sh). 3.389(q, J=7Hz, 2H); 3.861(t, J=7Hz, 2H); 6.084(quint, J=2Hz,       Cl, 7.14 (7.42) 1455 1H); 7.18-7.30(m, 3H); 7.346(s, 1H); 8.499(brs,      1H) Ia-43 102.0-103.5 C.sub.18 H.sub.22 N.sub.3 O.sub.2 Cl (CHCl.sub.3)      (CDCl.sub.3)  (ethyl C, 61.99 (62.15) 3310, 1715, 1680 2.024(quint, J=      7Hz, 2H); 2.55-2.64(m, 4H); 2.673(t, J=7Hz, 2H);  acetate/ H, 6.31      (6.37) 1595, 1545, 1489 2.766(t, J=6Hz, 2H); 3.218(q, J=3Hz, 2H);      3.504(q, J=6Hz, 2H);  Et.sub.2 O) N, 1207 (12.08) 1460 3.860(t, J=7Hz,      2H); 6.082(quint, J=2Hz, 1H); 7.19-7.27(m, 3H);   Cl, 9.96 (10.19)      7.361(s, 1H); 8.615(brs. 1H) Ia-44 140.5-142.0 C.sub.23 H.sub.29 N.sub.3      O.sub.6 Cl.1/5H.sub.2 O (Nujol) (CDCl.sub.3)  (iPrOH) C, 57.35 (57.37)      3280, 2580, 2360 1.846(quint, J=7Hz, 2H); 2.048(quint, J=8Hz, 2H);      2.47-2.51(m,  (maleate) H, 5.87 (5.94) 1715, 1690, 1620 2H); 2.566(t,      J=8Hz, 2H); 2.606(t, J=8Hz, 2H); 2.728(t, J=6Hz,   N, 8.67 (8.37) (sh),      1460 2H); 5.656(quint, J=2Hz); 7.15-7.37(m, 4H); 8.510(brs, 1H)   Cl,      7.72 (7.36) Ia-45 142.0-143.5 C.sub.23 H.sub.36 N.sub.3 O.sub.6 Cl      (Nujol) (CDCl.sub.3)  (maleate) C, 56.54 (56.96) 3300, 2580-2400,      2.007(t, quint, J=7Hz, 2H); 2.35-2.57(m, 2H); 2.610(t, J=8Hz);   H, 5.89      (5.65) 1710, 1682, 1617 2.746(g, J=7Hz, 2H); 2.830(t, J=6Hz, 2H);      3.723(q. J=3Hz, 2H);   N, 8.79 (9.06) 1565, 1528 3.544(q, J=6Hz, 2H);      3.869(t, J=7Hz, 2H); 5.656(q, J=2Hz, 1H);   Cl, 7.98 (7.64)  7.15-7.37(m,       4H); 8.626(brs, 1H) Ia-46 216.0-217.5 C.sub.21 H.sub.25 N.sub.3 O.sub.6      Cl.sub.2.1/5H.sub.2 O (Nujol) (CDCl.sub.3)  (MeOH) C, 51.31 (51.48)      3340, 1710, 1645 1.807(quint, J=7Hz, 2H); 2.027(quint, J=8Hz, 2H);      2.48-2.56(m,  (oxalate) H, 5.15 (5.23) 1588, 1562, 1538 4H); 2.599(t,      J=8Hz, 2H); 2.689(t, J=6Hz, 2H); 3.155(q, J=3Hz,   N, 8.53 (8.58) 1488,      1460, 1420 2H); 3.383(q, J=7Hz, 2H); 3.859(t, J=7Hz, 2H); 6.111(quint.      J=2   Cl, 14.65 (14.47)  Hz, 1H); 7.20-7.25(m, 3H); 8.510(brs, 1H) Ia-47      99.0-100.0 C.sub.19 H.sub.24 N.sub.3 O.sub.2       Br: (CHCl.sub.3) (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 --Et.sub.2 O) C,      56.32 (56.16) 33.20, 1712, 1680 1.819(quint, J=7Hz, 2H); 2.023(quint,      J=7Hz, 2H); 2.49-2.56(m,   H, 6.04 (5.95) 1545, 1489, 1465 4H); 2.598(t,      J=7Hz, 2H); 2.699(t, J=6Hz, 2H); 3.145(q, J=3Hz,   N, 10.35 (10.34)      (sh), 1460, 1440 2H); 3.386(q, J=6Hz, 2H); 3.861(t, J=7Hz, 2H); 6.064(qui      nt, J=2   Br, 19.59 (19.67)  Hz, 1H); 7.247(d, J=8Hz, 2H); 7.462(d,      J=8Hz, 2H); 8.495(brs, 1H) Ia-48 97.5-98.5 C.sub.19 H.sub.24 N.sub.3      O.sub.2 F: (CHCl.sub.3) (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 --Et.sub.2 O)      H, 7.03 (7.00) 3320, 1713, 1682 1.825(quint, J=7Hz, 2H); 2.021(quint,      J=8Hz, 2H); 2.49-2.56(m,   N, 12.07 (12.16) 1605, 1545, 1510 4H);      2.597(t, J=8Hz, 2H); 2.705(t, J=6Hz); 3.152(q. J=3Hz, 2H);   F, 5.57      l(5.50) 1490, 1460 3.389(q, J=7Hz, 2H); 3.862(t, J=7Hz, 2H); 5.998(quint,       J=2Hz,     1H); 6.992(t, J=8Hz, 2H); 7.343(d-d, J.sub.1 =8Hz, J.sub.1      =5Hz,     2H); 8.495(brs, 1H) Ia-49 136.0-136.5 C.sub.22 H.sub.26      N.sub.3 O.sub.6 F: (Nujol) (CDCl.sub.3)  (iPrOH) C, 59.13 (59.05) 3300,      2600(br) 2.028(quint, J=8Hz, 2H); 2.50-2.60(m, 4H); 2.674(t, J=7Hz, 2H);       (maleate) N, 9.31 (9.39) 1720, 1675, 1610 2.741(t, J=5Hz, 2H); 3.216(q,      J=3Hz, 2H); 3.551(q, J=6Hz, 2H);   F, 4.48 (4.25) 1515 3.866(t, L=7Hz,      2H); 5.993(quint, J=2Hz, 1H); 6.997(t, J=9Hz,     2H); 7.350(d-d,      J.sub.1 =9Hz, J.sub. 2 =5Hz, 2H); 8.615(brs, 1H) Ia-50 185.0-188.0      C.sub.20 H.sub.23 N.sub.3 O.sub.2 ClF.sub.3.HCl.1/5H.sub.2 O(Nujol)      (CDCl.sub.3)  (iPrOH--MEOH--Et.sub.2 O) C, 50.92 (51.11) 3320, 2670,      2550 1.822(quint, J=7Hz, 2H); 2.030(quint, J=8Hz, 2H); 2.544(t, J=8Hz,      (hydro-chloride) H, 515 (5.23) 2420, 1710 2H); 2.55-2.60(m, 2H);      2.602(t, J=8Hz, 2H); 2.718(t, J=5Hz, 2H);   N, 8.71 (8.94)  2H);      3.177(q. J=2Hz, 2H); 3.393(q. J=7Hz, 2H); 3.865(t, J=7Hz.   Cl, 14.95      (15.08)  2H); 6.10-6.18(m, 1H); 7.40-7.50(m, 2H); 7.679(brs, 1H); 8511      F, 11.83 (12.12)  (brs, 1H) Ia-51 213.0-215.0 C.sub.19 H.sub.21 N.sub.3      O.sub.2 ClF.sub.3.HCl (Nujol) (CDCl.sub.3)  (iPrOH--MeOH) C, 50.38      (50.45) 3500, 2520, 1704 2.030(quint, J=7Hz, 2H); 2.50-2.60(m, 2H);      2.597(t, J=8hz, 2H);  (hydro-chloride) H, 4.90 (4.90) 1683, 1548, 1493      2.678(t, J=6Hz, 2H); 2.777(t, J=6Hz, 2H); 3.236(q, J=3Hz, 2H);   N, 9.22      (9.29) 1462 3.504(q, J=6Hz, 2H); 3.864(t, J=7Hz, 2H); 6.10-6.16l(m, 1H);        Cl, 15.65 (15.68)  7.40-7.50(m, 2H); 7.685(brs, 1H) Ia-52 83.0-84.0      C.sub.17 H.sub.22 N.sub.3 O.sub.2 SCl (CHCl.sub.3) (CDCl.sub.3)      (CH.sub.2 Cl.sub.2 --Et.sub.2 O)C, 55.38 (55.50) 3320, 1712, 1680      1.801(quint, J=7Hz, 2H); 2.024(quint, J=7Hz, 2H); 2.50(brs, 2H)   H, 596      (6.03) 1545 2.520(t, J=7Hz, 2H); 2.596(t, J=8Hz, 2H); 2.670(t, J=6Hz,      2H);   N, 11.51 (11.42)  3.119(q, J=3Hz, 2H); 3.376(q, J=7Hz, 2H);      3.857(t, J=7Hz, 2H);   S, 8.69 (8.71)  5.953(quint, J=2Hz, 1H); 6.688(d,      J=4Hz, 1H); 6.756(d, J=4Hz,   Cl, 9.69 (9.64)  2H); 8.485(brs, 1H) Ia-53      156.5-157.5 C.sub.21 H.sub.25 N.sub.3 O.sub.6 SCl.sub.2 : (Nujol)      (CDCl.sub.3)  (iPrOH) C, 48.58 (48.65) 3300, 1708, 1680 1.808(quint,      J=7Hz, 2H); 2.030(quint, J=7Hz, 2H); 2.48-2.56(m,  (maleate) H, 4.89      (4.86) 1585, 1535 4H); 2.604(t, J=8Hz, 2H); 2.659(t, J=6Hz, 2H);      3.136(q, J=3Hz,   N, 8.02 (8.11)  2H); 3.383(q, J=7Hz, 2H); 3.862(t,      J=7Hz, 2H); 5.995(quint, J=2   S, 5.92 (6.18)  Hz, 1H); 6.712(s, 1H);      8.497(brs, 1H) Ia-54 144.0-145.0 C.sub.24 H.sub.30 N.sub.3 O.sub.6 Cl      (Nujol) (CDCl.sub.3)  (iPrOH) C, 58.44 (58.59) 3280, 2400-2280, 1.78-1.91      (m, 6H); 2.45-2.60(m, 6H); 2.703(t, J=6Hz, 2H); 3.161  (maleate) H, 6.05      (6.15) 1692, 1650, 1622 (q, J=3Hz, 2H); 3.383(q, J=7Hz, 2H); 3.76-3.83(m,       2H); 6.056   N, 8.52 (8.54) 1575, 1522, 1495 (quint, J=2Hz, 1H); 7.264,      7.322(ABq, J=9Hz, 4H); 9.449(brs, 1H)   Cl, 7.33 (7.21) Ia-55 134.0-135.5       C.sub.19 H.sub.24 N.sub.3 O.sub.2 Cl (CHCl.sub.2) (CDCl.sub.3)      (CH.sub.2 Cl.sub.2 --Et.sub.2 O) C, 62.84 (63.06) 3280, 1795, 1645      1.78-1.85(m, 4H); 2.45-2.60(m, 4H); 2.680(t, J=7Hz, 2H); 2.770   H, 6.67      (6.68) 1527, 1495, 1480 (t, J=6Hz, 2H); 3.238(q, J=2Hz,2H); 3.513(q,      J=7Hz, 2H); 3.80-   N, 11.41 (11.61) 1463, 1450 3.83(m, 2H); 6.051(quint,       J=2Hz, 1H); 7.24-7.35(m, 4H); 9.521   Cl, 10.05 (9.80)  (brs, 1H) Ia-56      192.5-193.5 C.sub.24 H.sub.30 N.sub.2.2C.sub.4 H.sub.4 O.sub.4 (Nujol)      (CDCl.sub.3) (free)  (CH.sub.2 Cl.sub.2 --MeOH- C, 65,32 (65.51) 2340,      1916, 1707 0.966(d, J=5Hz, 3H); 1.314(s, 9H); 1.43-1.57(m, 3H); 1.67-1.78        iPrOH) H, 7.84 (7.90) 1619, 1563, 1542 (m, 2H); 1.930(quint, J=7Hz,      2H); 2.239(t, J=12Hz, 2H); 2.49-2.58  (di-maleate) N, 4.77 (4.77) 1481,      1460, 1446 (m, 2H); 2.528(t, J=7Hz, 2H); 2.63-2.74(m, 4H); 3.14-3.21      1378 (m, 4H); 6.027(quint, J=1Hz, 1H); 7.330(ABq, J=8Hz, 4H) Ia-57      191.5-193.0 C.sub.21 H.sub.32 N.sub.2.2C.sub.4 H.sub.4 O.sub.4 (Nujol)      (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 --MeOH- C, 63.75 (63.95) 2340, 1995,      1709 0.980(d, J=5Hz, 3H); 1.48-1.66(m, 3H); 1.70-1.82(m, 2H); 1.953      iPrOH) H, 7.31 (7.40) 1621, 1525(sh), (quint, J=7Hz, 2H); 2,333(s, 3H);      2.357(t, J=12Hz, 2H); 2.544  di-maleate) N, 5.16 (5.14) 1510(sh), 1483      (t, J=7Hz, 4H); 2.715(t, J=8Hz, 2H); 2.78-2.84(m, 2H); 3.160 (q,      1462, 1449(sh), J=3Hz, 1H); 3.298(d, J=12Hz); 6.013(quint, J=1Hz, 1H);      7.123.7.2    1379 84 (ABq, J=8Hz, 4H) Ia-58 190.0-192.0 C.sub.23      H.sub.36 N.sub.2.2C.sub.4 H.sub.4       O.sub.4 (Nujol) (CDCl.sub.3)  (MeOH-iPrOH) C, 64.92 (65.02) 2360, 1997,      1708 1.324(s, 9H); 1.50-2.00(m, 8H); 2.50-2.80(m, 12H); 3.200(q, J=      (di-maleate) H, 7.68 (7.74) 1619, 1570, 1535 3Hz, 2H); 6.056(s, 1H);      7.347(ABq, J=8Hz, 4H)   N, 4.91 (4.89) 1480, 1457, 1448    (sh), 1379      Ia-59 193.0-195.0 C.sub.23 H.sub.37 N.sub.3.3C.sub.4 H.sub.4 O.sub.4      (Nujol) (CDCl.sub.3)  (CHCl.sub.3 --MeOH) C, 59.39 (59.58) 2335, 1995,      1706 1.313(s, 9H); 1.786(quint, J=7Hz, 2H); 2.296(s, 3H); 2.37-2.60      (tri-maleate) H, 6.95 (7.03) 1621, 1568, 1542 (m, 17H); 2.703(t, J=5Hz,      2H); 3.158(q, J=3Hz, 2H); 6.028   N. 602 (5.96) (sh), 1478, 1460 quint,      J=1Hz, 1H); 7.382(ABq. J=8Hz, 4H)    1439, 1380(sh) Ia-60 75.0-77.0      C.sub.16 H.sub.21 NO (Nujol) (CDCl.sub.3)  (Et.sub.2 O- C, 77.94 (77.88)      3110, 3023, 2773 1.791(quint, J=7Hz, 2H); 2.332(s, 3H); 2.50-2.60(m,      2H); 2.735  n-hexane) H, 9.16 (9.15) 1518, 1467, 1412 (t, J=6Hz, 2H);      2.775(t, J=6Hz, 2H); 3.221(q, J=3Hz, 2H); 3.834   N, 6.22 (6.05) 1397,      1379 (t, J=5Hz, 2H); 6.001(quint, J=2Hz, 1H); 7.123.7.272(ABq, J=8Hz,       4H) Ia-61 115.0-116.0 C.sub.20 H.sub.39 N.sub.3 O.C.sub.4 H.sub.4      O.sub.4 (Nujol) (CD.sub.3 OD)  (iPrOH-- Et.sub.2 O) C, 64.88 (64.99)      3405, 2720, 2570 1.87-12.05(m, 6H); 2.333(s, 3H); 2.886(brs, 2H);      3.21-3.36(m,  (maleate) H, 7.54 (7.50) 2295, 1642, 1580 1H); 3.522(brs,      2H); 3.913(s, 2H); 6.099(s, 1H); 6.245(s, 2H);   N, 9.42 (9.47) 1538,      1499, 1457 7.188.7.369(ABq, J=9Hz, 4H) Ia-62 164.0-166.0 C.sub.25      H.sub.31 N.sub.3 O.C.sub.4 H.sub.4 O.sub.4 (Nujol) (CD.sub.3 OD)      (MeOH--Et.sub.2 O) C, 68.89 (68.89) 3403, 3037, 2330 1.88-2.06(m, 4H);      2.951(brs, 2H); 3.20-3.40(m, 6H); 3.557(brs,  (maleate) H, 6.97 (6.98)      1700, 1640, 1578 1H); 3.959(brs, 2H); 6.220(s, 1H); 6.248(s, 2H);      7.30-7.70(m,   N, 8.30 (8.31) 1537, 1498, 1457 9H)    (sh), 1449, 1409      Ia-63 150.0-151.5 C.sub.24 H.sub.28 N.sub.5 OF.sub.3 (CHCl.sub.3)      (CDCl.sub.3)  (CH.sub.2 Cl.sub.2 --Et.sub.2 O) C, 62.55 (62.73) 1632,      1617(sh), 1.940(quint, J=7Hz, 2H); 2.450(t, J=8Hz, 2H); 2.547(t, J=7Hz,       H, 6.08 (6.14) 1588, 1552, 1495 2H); 5.565(brs, 2H); 2.727(t, J=6Hz,      2H); 6.142(s, 1H); 6.515   N, 1513 (15.24) 1437 (t, J=5Hz, 1H); 7.448.7.5      40(ABq, J=8Hz, 4H); 8.301(d, J=5Hz, 2H)   F, 12.36 (12.40) Ia-64      108.0-109.0 C.sub.19 H.sub.26 N.sub.2 O (CHCl.sub.3) (CDCl.sub.3)      (CH.sub.2 Cl.sub.2 --Et.sub.2 O- C 76.26 (76.47) 1625, 1512, 1466      1.78-2.04(m, 4H); 2,332(s, 3H); 2.574(t, J=8Hz, 4H); 2.765(t,  n-hexane)      H, 8.70 (8.78) 1448, 1378 J=6Hz, 2H); 2.881(t, J=8Hz, 2H); 3.211(q,      J=3Hz, 2H); 3.448(t,   N, 9.32 (9.39)  J=6Hz, 2H); 3.477(t, J=6Hz, 2H);      6.02(quint, J=2Hz, 1H); 7.122.7     .285 (ABz, J=8Hz, 4H) Ia-65 183.0-190      .0 C.sub.22 H.sub.31 N.sub.3       O.sub.2.HCl (Nujol) (CDCl.sub.3)  (MeOH--Et.sub.2 O) C, 65.06 (65.09)      3310, 2725, 2670 1.313(s, 9H); 2.018(quint, J=8Hz, 2H); 2.52-2.64(m,      6H); 2.678  (hydro-chloride) H, 8.04 (7.95) 2405, 1709, 1688 (6, J=7Hz,      2H); 2.774(t, J=6Hz, 2H); 3.212.3.242(ABq, J=3Hz, 2H)   N, 10.38 (10.35)      1549, 1519, 1488 3.545.3.484(ABz, J=7Hz, 2H); 3.859(t, J=7Hz, 2H);      6.029(quint,   Cl, 8.46 (8.73) 1459, 1430, 1412 J=2Hz, 1H); 7.332(s,      4H); 8.604(brs, 1H)    1392 Ia-66 216.0-219.0 C.sub.18 H.sub.21 N.sub.3      O.sub.2 Cl.sub.2.HCl (Nujol) (CDCl.sub.3)  (MeOH--Et.sub.2 O) C, 51.66      (51.63) 3290, 2510, 1712 2.024(quint, J=7Hz, 2H); 2.45-2.55(m, 2H);      2.594(t, J=8Hz, 2H);  (hydro-chloride) H, 5.34 (5.30) 1672, 1521      2.665(t, J=8Hz, 2H), 2.754(t, J=6Hz, 2H); 3.214(q, J=3Hz, 2H);   N,      10.01 (10.03)  3.497(q, J=6Hz, 2H); 3.860(t, J=7Hz, 2H); 6.0-6.14(m,      1H); 7.208   Cl, 25.12 (25.40)  (dd, J.sub.1 =8Hz, J.sub.2 =2Hz, 1H);      7.365(d, J=8Hz, 1H); 7.450(d, J=2Hz,     1H); 8.615(brs, 1H) Ia-67      238.0-248.0 C.sub.19 H.sub.22 N.sub.3 O.sub.2 F.sub.3.HCl (Nujol)      (CDCl.sub.3)  (MeOH--Et.sub.2 O) C, 54.43 (54.61) 3310, 2930, 2860      2.032(quint, J=8Hz, 2H); 2.50-2.66(m, 4H); 2.69(t, J=6Hz, 2H);  (hydro-ch      loride) H, 5.59 (5.55) 2460, 1711, 1687 2,722(t, J=6Hz, 2H); 3.256(q,      J=3Hz, 2H); 3.518(q, J=6Hz, 2H);   N, 9.89 (10.06) 1617, 1541 3.868(t,      J=7Hz, 2H); 6.14-6.17(m, 1H); 7.478. 7.567(ABq, J=9Hz,   Cl, 8.45 (8.48)       4H); 8.625(brs, 1H) Ia-68 228.0-232.0 C.sub.18 H.sub.22 N.sub.3 O.sub.2      Br.HCl (Nujol) (CD.sub.3 OD)  (MeOH--Et.sub.2 O) C, 50.89 (50.52) 3320,      2920, 2860 2.029(quint, J=8Hz, 2H); 2.50-2.60(m, 2H); 2.598(t, J=8Hz,      2H);  (hydro-chloride) H, 5.58 (5.41) 2460, 1710, 1685 2.675(6, J=7Hz,      2H); 2.769(t, J=6Hz, 2H); 3.216(q, J=3Hz, 2H);   N, 9.90 (9.80) 1537      3.509(q, J=6Hz, 2H); 3.865(t, J=7Hz, 2H); 6.04-6.08(m, 1H); 7.429,   Cl,      8.22 (8.27)  7.247(ABq, J=9Hz, 4H); 8.611(brs, 1H) Ia-69 205.0-210.0      C.sub.22 H.sub.27 N.sub.3       O.sub.2.HCl (Nujol) (CDCl.sub.3)  (MeOH--Et.sub.2 O) C, 67.72 (67.67)      3305, 3045, 2415 2.205(quint, J=8Hz, 2H); 2.54-2.66(m, 4H); 2.695(t,      J=7Hz, 2H);  (hydro-chloride) H, 6.64 (6.63) 2405, 1702, 1679 2.803(t,      J=6Hz, 2H); 3.261(q, J=3Hz, 2H); 3.558, 3.497(ABq, J=7   N, 9.80 (9.87)      1578, 1540, 1488 Hz, 2H); 3.865(t, J=7Hz, 2H); 6.128(quint, J=2Hz, 1H);      7.28-7.67   Cl, 8.10 (8.32) 1457, 1444, 1420 (m, 9H); 8.624(brs,      *a solvent for recrystallization

EXAMPLE 72 1-{3-(1-Methyl-2-oxo-imidazolidin-1-yl)propyl}-4-(4-tolyl)-1,2,5,6-tetrahydropyridine (I a-72) ##STR49##

(1) A mixture of 870 mg of the compound (I a-60) and 8.0 ml of thionylchloride is stirred at room temperature for 2 hours. After removal of the excess reagent under reduced pressure, the residue was washed with Et₂ O and dried under reduced pressure to prepare 1.067 g (Yield: 99.2%) of the compound (V-3) as pale yellow powder.

IR(CHCl₃) cm⁻¹ : 1600, 1510, 1460, 1410

NMR (CDCl₃): 2.046 (quint, J=7 Hz, 2H); 2.334 (s, 3H); 2.54-2.64 (m, 2H); 2.629 (t, J=7H, 2H); 2.723 (t, J=5 Hz, 2H); 3.173 (q, J=2 Hz, 2H); 3.630 (t, J=7 Hz, 2H); 6.023 (quint, J=2 Hz, 1H); 7.123, 7.287 (ABq, J=8 Hz, 4H)

(2) To a solution of 266 mg of 1-methyl-2-oxo-imidazolidine in 5 ml of DMF was added 115 mg of 60% NaH under ice-cooling. After stirring at room temperature for 20 minutes, a solution of 553 mg of the compound (V-3) in 4 ml of DMF was added to the reaction mixture and stirred at room temperature for 90.5 hours. The reaction mixture was concentrated under reduced pressure and poured into d-HCl. The aqueous layer is made alkaline with NaHCO₃, extracted with CHCl₃ --MeOH (19/1), dried over MgSO₄, and evaporated. The residue is subjected to column chromatography with silica gel, eluting with CHCl₃ --MeOH (19/1) to prepare 491 mg of the compound (I a-72). The maleate is recrystallized from iPrOH-Et₂ O to prepare 439 mg (Yield: 45.8%) of colorless needles. mp. 126.5°-128.0° C.

Anal Calcd. (%) for C₁₉ H₂₇ N₃ O.C₄ H₄ O₄.1/5H₂ O: C, 63.73; H, 7.20; N, 9.61. Found: C, 63.78; H, 7.31; N, 9.70.

IR (CHCl₃): 2450, 2340, 1910, 1689, 1622, 1502, 1451, 1409, 1382

NMR (CDCl₃): 1.797 (quint, J=8 Hz, 2H); 2.329 (s, 3H); 2.46-2.62 (m, 4H); 2.712 (t, J=5 Hz, 2H); 2.790 (s, 3H); 3.166 (q, J=3 Hz, 2H); 3.255 (t, J=7 Hz, 2H); 3.295 (s, 4H); 6.014 (quint, J=2 Hz, 1H ); 7.117, 7.283 (ABq, J=8 Hz, 4H)

EXAMPLE 73-91

The compounds (V) obtained in Example 19-21 are reacted in the same manner as Example 72 to prepare the compound (Ia). The reaction conditions are shown in Table 10.

                                      TABLE 10                                     __________________________________________________________________________      ##STR50##                                                                     Ex.                     reaction                                                                              purification                                                                             product                               No.                                                                               (V) (VIII)      solvent                                                                             condition                                                                             condition mg (Yield)                                                                           m.p. (°C.)                                                                    IR                        __________________________________________________________________________     73 (V-3) 742 mg                                                                        ##STR51##  DMF 5 ml                                                                            100° C. 47 min.                                                                CH.sub.2 Cl.sub.2 /MeOH = 19/1                                                            Ia-73.sup.*1  602                                                                   119.0- 121.0 (iPrOH)                                                                 (CHCl.sub.3) 2455,                                                             2310, 1677 1622,                                                               1512, 1497 1464,                                                               1380, 1351                74 (V-2) 1.02 g                                                                        ##STR52##  DMF 10 ml                                                                           100° C. 25 hr.                                                                 toluene/ acetone = 3/1-1/1                                                                Ia-74.sup.*1  266                                                                   152.0- 154.0 (MeOH-                                                            Et.sub.2 O)                                                                          (Nujol) 2700-1750(br)                                                          , 1695, 1663, 1619                                                             1532, 1463, 1412                                                               1378, 1358                75 (V-3) 500 mg                                                                        ##STR53##  DMF 8 ml                                                                            70° C. 10 hr.                                                                  CH.sub.2 Cl.sub.2 /MeOH = 39/1                                                            Ia-75 409 mg (62.4%)                                                                98.0- 100.0 (CDCl.sub.3 -                                                      MeOH) (CHCl.sub.3) 3690,                                                             1771, 1602 1511,                                                               1488, 1454 1429,                                                               1416, 1384                76 (V-3) 500 mg                                                                        ##STR54##  DMF 8 ml                                                                            80° C.  15 hr.                                                                 toluene/ acetone = 4/1                                                                    Ia-76.sup.*1  130                                                                   154.0- 155.5 (MeOH-                                                            Et.sub.2 O)                                                                          (Nujol) 3050, 2660,                                                            2615 2570, 2480,                                                               2410 1606, 1590,                                                               1578 1517, 1498,                                                               1479, 1447, 1423,                                                              1398 1376                 77 (V-3) 650 mg                                                                        ##STR55##  DMF 6 ml                                                                            100° C. 5 hr.                                                                  toluene/ acetone = 9/1                                                                    Ia-77.sup.*1  1.08                                                                  174.0- 176.0 (dec.) (MeOH-                                                     t.sub.2 O)                                                                           (CHCl.sub.3) 3685,                                                             2495, 3350 2700-1800                                                           (br),  1778, 1707,                                                             1621 1511, 1496,                                                               1446 1395                 78 (V-2) 440 mg                                                                        ##STR56##  DMF 8 ml                                                                            110° C. 6 hr. 20 min.                                                          toluene/ acetone = 9/1                                                                    Ia-78.sup.*1  135                                                                   149.0- 151.0 MeOH-                                                             Et.sub.2 O)                                                                          (CHCl.sub.3) 3575,                                                             3338                      79 (V-3)                                                                              NaOPh 207 mg                                                                               DMF  70° C.                                                                         toluene/  Ia-79.sup.*1                                                                         148.0-                                                                               (Nujol)                      0.828 g         8 ml 3 hr. 10 min.                                                                         acetone = 9/1                                                                            562 mg                                                                               150.0 2720, 2370, 1701                                                   (66.3%)                                                                              (MeOH-                                                                               1620, 1598, 1584                                                         Et.sub.2 O-                                                                          1499, 1467,                                                              iPrOH)                                                                               1458(sh), 1387            80 (V-3) 942 mg                                                                        ##STR57##  --   150° C. 8 hr. 15 min.                                                          toluene/ acetone = 19/1-9/1                                                               Ia-80 930 mg (54.4%)                                                                148.0- 150.0 (iPrOH-                                                           Et.sub.2 O)                                                                          (Nujol) 2720,                                                                  2575(sh), 2490(sh),                                                            2330, 1708, 1652,                                                              1600 1571, 1502,                                                               1459                      81 (V-3) 624 mg                                                                        ##STR58##  --   150° C. 4 hr. 10 min.                                                          CH.sub.2 Cl.sub.2 MeOH = 19/1                                                             Ia-81 963 mg (66.6%)                                                                191.0- 192.0 (dec.) (MeOH-                                                     t.sub.2 O)                                                                           (Nujol) 3030, 2720,                                                            2278 1711, 1623,                                                               15722 1532,                                                                    1513(sh), 1485,                                                                1463, 1435                82 (V-3)                                                                              HN(iBu), 1.358 g                                                                           --   20 hr. CH.sub.2 Cl.sub.2 MeOH =                                                                 Ia-82.sup.*1                                                                         140.5-                                                                               (Nujol)                      517 mg               reflux 49/1      457 mg                                                                               142.5 2710, 2500, 1706                                                   (38.4%)                                                                              (CH.sub.2 Cl.sub.2                                                                   1572, 1480, 1455                                                         Et.sub.2 O)                                                                          1375                      83 (V-3)                                                                              H.sub.2 N(iBu), 1.02 ml                                                                    --   10.5 hr.                                                                              CH.sub.2 Cl.sub.2 MeOH/                                                                  Ia-83.sup.*1                                                                         179.5-                                                                               (Nujol)                      511 mg               reflux NH.sub.4 OH =                                                                            471 mg                                                                               182.5 3340, 2780, 2545                                         128/12/1  (44.4%)                                                                              (CH.sub.2 Cl.sub.2                                                                   2460, 1699, 1618                                                         Et.sub.2 O)                                                                          1577, 1474, 1458                                                               1441, 1381                84 (V-3) 466 mg                                                                        ##STR59##  --   50° C. 3 hr.                                                                   CH.sub.2 Cl.sub.2 MeOH/ NH.sub.4 OH =                                          128/16/1- 32/4/0.5                                                                        Ia-84.sup.*1  225                                                                   180.0- 181.0                                                                         (Nujol) 2340, 1709,                                                            1550 1458, 1377,                                                               156                       85 (V-3)                                                                              H.sub.2 N(CH.sub.2).sub.2 N(iPr),                                                          --   105° C.                                                                        CH.sub.2 Cl.sub.2 MeOH/                                                                  Ia-85.sup.*1                                                                         125.0-                                                                               (Nujol)                      511 mg                                                                             1.054 g          7 hr.  NH.sub.4 OH =                                                                            436 mg                                                                               127.0 2668, 2500, 2400                                         128/16/1- (32.0%)     (sh), 1702, 1619                                         64/8/1                1570, 1462, 1378          86 (V-2)                                                                              HN(iBu), 1.50 g                                                                            --   32 hr. CH.sub.2 Cl.sub.2 MeOH =                                                                 Ia-86.sup.*1                                                                         135.0-                                                                               (Nujol)                      654 mg               reflux 49/1-19/1 338 mg                                                                               136.5 2420, 1707, 1616                                                   (27.1%)     1572, 1485, 1456                                                               1377                      87 (V-2)                                                                              HN(iBu), 1.1 ml                                                                            --   32 hr. CH.sub.2 Cl.sub.2 MeOH =                                                                 Ia-87.sup.*1                                                                         135.0-                                                                               (Nujol)                      645 mg               reflux 49/1-19/1 338 mg                                                                               136.0 2420, 1707, 1616                                                   (27.1%)                                                                              (MeOH-                                                                               1572, 1485, 1456                                                         Et.sub.2 O)                                                                          1377                      88 (V-2) 1.05 g                                                                        ##STR60##  --   room temperature 32.5 hr.                                                             CH.sub.2 Cl.sub.2 MeOH/ NH.sub.4 OH =                                          128/16/1- 32/4/0.5                                                                        Ia-88.sup.*1  1.034                                                                 176.0- 178.0 (MeOH)                                                                  (Nujol) 3483, 2723,                                                            2679 2587, 2415,                                                               1703 1608, 1570,                                                               1478 1460, 1412,                                                               1382                      89 (V-2) 621 mg                                                                        ##STR61##  --   room temperature 5 days                                                               CH.sub.2 Cl.sub.2 MeOH/ NH.sub.4 OH =                                          128/16/1   Ia-89.sup.*1  800                                                                   190.0- 191.0 (dec.)                                                                  (Nujol) 2355, 1711,                                                            1620 1577, 1543,                                                               1479 (sh), 1461,                                                               1378                      90 (V-1) 828 mg                                                                        ##STR62##  --   150° C. 3 hr.                                                                  CH.sub.2 Cl.sub.2 MeOH = 29/1-19/1                                                        Ia-90.sup.*1  1.025                                                                 183.5- 185.0 (CHCl.sub.3 -                                                     eOH)  (Nujol) 2340, 1708,                                                            1619 1568, 1528(sh),                                                           485, 1461                 91 (V-1)                                                                              HN(iBu), 3.76 ml                                                                           --   33 hr. CH.sub.2 Cl.sub.2 MeOH =                                                                 Ia-91.sup.*1                                                                         176.5-                                                                               (Nujol)                      628 mg               reflux 49/1-19/1 685 mg                                                                               178.0 2620, 2510, 1690                                                   (51.6%)                                                                              (dec.)                                                                               1657, 1618, 1579                                                         (MeOH-                                                                               1533, 1488, 1460                                                         Et.sub.2 O)                                                                          1409,                     __________________________________________________________________________                                                          1378                       .sup.*1 : maleate                                                        

EXAMPLE 92 4-(4-tert-Butylphenyl)-1-[3-{4-(pyrimidin-2-yl)piperazin-1-yl}propyl]-1,2,5,6-tetrahydropyridine (I a-92) ##STR63##

(1) A mixture of 1.1 g of 3-{4-pyrimidin-2-yl)piperazin-1-yl}propylchloride, 1.07 g of the compound (II-6), 1.26 g of K₂ CO₃, and 1.03 g of NaI in 12 ml of DMF is stirred at 100° C. for 4 hours. The reaction mixture is poured into ice-water and extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated. The residue is purified by silica gel chromatography (CH₂ Cl₂ /MeOH=10/1) followed by recrystallization from CH₂ Cl₂ -Et₂ O to prepare 1.70 g (Yield: 85%) of the compound (III-56). mp. 215.0°-225.0° C. (dec.)

(2) A solution of 1.58 g of the compound (III-56) in 15 ml of CF₃ COOH is refluxed for 3.5 hours. After removal of the excess reagent, the residue is poured into ice-cooled aq.NaHCO₃ and extracted. The organic layer is dried over Na₂ SO₄ and evaporated under reduced pressure. The oily residue is purified by column chromatography with silica gel, eluting with CH₂ Cl₂ /MeOH (10/1-5/1) to prepare 1.44 g (Yield: 95%) of the compound (I a-92) as crystals (mp. 79.0°-81.0° C.) The maleate is recrystallized from methanol to prepare colorless needles. mp. 209.0°-211.0° C. (dec.)

EXAMPLE 93-94

The reactions are performed in the same manner as Example 92 to prepare the compound (III) and (I a). The reaction conditions and physical constants are shown in Tables 11 and 12.

                                      TABLE 11                                     __________________________________________________________________________     (Step 1)                                                                        ##STR64##                                                                     Ex.                 DMF K.sub.2 CO.sub.3                                                                   NaI reaction                                                                              purification                                                                             g (Yield)                     No.                                                                               (II)                                                                               R(CH.sub.2)nY (VI)                                                                          (ml)                                                                               (g) (g) condition (1)                                                                         condition (1)                                                                            Compd.                                                                                m.p.                   __________________________________________________________________________                                                             (°C.)           93 (II-6) 980 mg                                                                       ##STR65##   20  1.16                                                                               0.94                                                                               105 6.5 hr.                                                                           CH.sub.2 Cl.sub.2 /MeOH                                                                  1.69 (92.6) (III-57)                                                                  129.0- 130.5                                                                   (CH.sub.2                                                                      Cl.sub.2 -                                                                     Et.sub.2 O)                                                                    (maleate)              94 (II-6) 2.67 g                                                                       ##STR66##   20  3.18                                                                               2.60                                                                               95-100 17 hr.                                                                         CH.sub.2 Cl.sub.2 /MeOH                                                        = 20/1-10/1                                                                              4.04 (93.3) (III-58)                                                                  137.0- 138.5                                                                   (CH.sub.2                                                                      Cl.sub.2 -                                                                     Et.sub.2 O)                                                                    (maleate)              __________________________________________________________________________

                                      TABLE 12                                     __________________________________________________________________________     (Step 2)                                                                       (III)            purification                                                                             (I a)                                               (g)  CF.sub.3 COOH                                                                        reflux time                                                                          condition g (Yield)                                                                           m.p. (°C.)                                                                    IR                                       __________________________________________________________________________     (III-57)                                                                            20 ml 4 hr. CH.sub.2 Cl.sub.2 /MeOH =                                                                I a-93                                                                              105-106                                                                              (Nujol)                                  1.50 g           20/1-10/1 1.40 g                                                                              (MeOH)                                                                               1710, 1622, 1598, 1575,                                             (97.4)     1495 (sh), 1480, 1462,                                                         1450, 1385, 1360                         (III-58)                                                                            10 ml 8 hr. CH.sub.2 Cl.sub.2 /MeOH =                                                                I a-94                                                                              213.0-                                                                               (Nujol)                                  0.88 g           20/1      maleate                                                                             214.5 2300, 1717, 1622, 1575,                                             0.74 g                                                                              (MeOH)                                                                               1535, 1500, 1465, 1458,                                             (97.5)     1450                                     __________________________________________________________________________

EXAMPLE 95 4-(4-Hydroxyphenyl)-1-{3-(4-morpholinyl)propyl}-1,2,5,6-tetrahydropyridine (I a-95) ##STR67##

(1) A mixture of 2.829 g of 4-(4-methoxyphenyl)-4-hydroxypiperidine, 2.02 ml of 3-bromopropylchloride, and 3.773 g of K₂ CO₃ in 30 ml of DMF is stirred at room temperature for 3 hours. The reaction mixture is poured into ice-water and extracted with ethyl acetate. The organic layer is dried and evaporated under reduced pressure to prepare 4:525 g of pale yellow solid. Purification is conducted by column chromatography with silica gel; eluting with CH₂ Cl₂ /MeOH (29/1-5/1) to prepare 3.316 g (Yield: 85.6%) of the compound (IV-8) as solid which is recrystallized from n-hexane-Et₂ O to prepare colorless needles. mp. 103.5°-105.0° C.

Anal Calcd. (%) for C₁₅ H₂₂ ClNO₂ : C,63.48; H,7.81; N,4.94; Cl,12.49Found : C,63.47; H,7.78; N,5.01; Cl,12.45.

IR (CHCl₃) : 3595, 1610, 1582, 1510, 1468, 1462, 1454, 1441, 1375

NMR (CDCl₃) δ: 1.761 (d-d, J₁ =14 Hz, J₂ =3 Hz, 2H); 1.998 (quint, J=7 Hz, 2H); 2.121 (t-d, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.475 (t-d, J₁ =12 Hz, J₂ =3 Hz, 2H); 2.560 (t, J=7 Hz, 2H); 2.782 (d-d, J₁ =14 Hz, J₂ =3 Hz, 2H); 3.618 (t, J=7 Hz, 2H); 3.805 (s, 3H); 6.866, 7.427 (ABq, J=9 Hz, 4H)

(2) To a solution of 3.176 g of the compound (IV-8) is added 3.17 ml of BBr₃ with stirring under ice-cooling. After refluxing for 1.5 hours, the reaction mixture is poured into ice-water and the aqueous layer is made alkaline with c.NH₄ OH and extracted with CH₂ Cl₂ /MeOH (4/1). The organic layer is dried and evaporated to dryness. The crude product is dissolved in 20 ml of CF₃ COOH and refluxed for 1 hour. The reaction mixture is concentrated under reduced pressure and poured into ice-water. The aqueous layer is made alkaline with c.NH₄ OH and extracted with CH₂ Cl₂ /MeOH (4/1). The organic layer is dried and evaporated to prepare 1.701 g (Yield: 57.2%) of the compound (V-6) as solid, which is recrystallized from MeOH-n-hexane to prepare the compound (V-6) as pale orange plates. mp. 208.0°-209.0° C.

Anal Calcd. (%) for C₁₄ H₁₈ ClNO: C,66.79; H,7.21; N,5.56; Cl,14.08. Found: C,66.79; H,7.26; N,5.52; Cl,14.25.

IR(Nujol): 3025, 2773, 2650, 2560, 1607, 1578, 1515, 1453, 1429, 1382

NMR (CDCl₃ --CD₃ OD) δ: 2.66 (quint, J=8 Hz, 2H); 2.47-2.76 (m, 4H); 2.774 (t, J=6 Hz, 2H); 3.200 (q, J=2 Hz, 2H); 3.637 (t, J=6 Hz, 2H); 5.972 (s, 1H); 6.803, 7.275 (ABq, J=9 Hz, 4H)

(3) A stirred mixture of 1.482 g of the compound (V-6) and 2.57 ml of morpholine is refluxed for 2 hr.15 min. After removal of the reagent, the residue is purified by column chromatography with silica gel, eluting with CH₂ Cl₂ /MeOH/NH₄ OH (128/16/1-64/8/1) to give 1.047 g (Yield: 58.8%) of the compound (I a-95) as a solid. The maleate is recrystallized from MeOH-Et₂ O to prepare pale yellow plates. mp. 166.0°-167.5° C. (d.)

Anal Calcd. (%) for C₁₈ H₂₆ N₂ O₂.2C₄ H₄ O₄ : C,58.22; H,6.48; N,5.35. Found: C,58.42; H,6.41; N,5.24.

IR (Nujol): 3230, 3063, 2725, 2355, 1715, 1625, 1579, 1519, 1464, 1387

NMR (CD₃ OD) δ: 2.13-2.35 (m, 2H); 2.866 (brs, 2H); 3.03-3.25 (m, 6H); 3.25-3.40 (m, 2H); 3.564 (t, J=6 Hz, 3H); 3.883 (t, J=5 Hz, 4H); 3.953 (brs, 2H); 5.999 (brs, 1H); 6.264 (s, 4H); 6.778, 7.320 (ABq, J=9 Hz, 4H)

EXAMPLE 96 4-(4-Hydroxyphenyl)-1-{3-(1-pyrrolidinyl)propyl}-1,2,5,6-tetrahydropyridine (I a-96) ##STR68##

A mixture of 1.50 g of the compound (V-6) and 4.97 ml of pyrrolidine is stirred at room temperature for 18.5 hours and treated in the same manner as Example 95 (3) to prepare 2.041 g (Yield: 66.1%) of the maleate of the compound (I a-96) as needles. mp. 145.0°-147.0° C. (dec.)

Anal Calcd. (%) for C₁₈ H₂₅ N₂ O.2C₄ H₄ O₄₄ : C, 60.03; H, 6.42; N,5.50. Found: C, 60.22; H, 6.61; N, 5.40.

IR (Nujol): 3230, 3041, 2710(sh), 2590, 2360, 1709, 1622, 1578, 1518, 1461, 1377

NMR (CD₃ OD) δ: 2.00-2.175 (m, 4H); 2.175-2.375 (m, 2H); 2.859 (brs, 2H); 3.23-3.48 (m, 8H); 3.542 (t, J=6 Hz, 3H); 3.992 (brs, 2H); 5.995 (brs, 1H); 6.257 (s, 4H); 6.778, 7.320 (ABq, J=8 Hz, 4H)

EXAMPLE 97 1-{3-(N-methylamino)propyl}-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine (I a-97) ##STR69##

A mixture of 3.00 g of the compound (V-6) and 11.84 ml of BuNH₂ is refluxed for 5 hours, and treated in the same manner as Example 96 to prepare 2.188 g (Yield: 63.7%) of the compound (I a-97) as needles. mp. 233.0°-236.0° C. (dec.)

IR (Nujol): 3425, 3055, 2778, 2670, 2582, 1665, 1613, 1590, 1515, 1471, 1453, 1439, 1428

NMR (CDCl₃): 0.920 (d, J=7 Hz, 6H); 1.92-2.18 (m, 3H); 2.554 (brs, 2H); 2.692 (d, J=7 Hz, 2H); 2.751 (t, J=6 Hz, 2H); 2.854 (t, 2H); 2.854 (t, J=6 Hz, 2H); 3.134 (t, J=6 Hz, 2H); 3.247 (brs, 2H); 5.922 (brs, 1H); 6.818, 7.194 (ABq, J=9 Hz, 4H)

EXAMPLE 98 1-{3-(N-isobutyl-N-methylamino)propyl}-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine (I a-98) ##STR70##

Treatment of 2.138 g of the compound (I a-97) in the same manner as Example 34 prepares 1.528 g (Yield: 70.1%) of the compound (I a-98) as solid, which is crystallized as maleate and recrystallized from MeOH-Et₂ O to prepare pale yellow plates. mp.150.0°-153.0° C. (dec.)

Anal Calcd. (%) for C₁₉ H₃₀ N₂ O.2C₄ H₄ O₄ : : C, 60.38; H, 7.16; N, 5.38. Found: C, 60.66; H, 7.16; N, 5.24.

IR (Nujol): 3235, 2700(sh), 2400, 1618, 1576, 1517, 1459, 1380 (sh), 1372(sh), 1359

NMR (CD₃ OD) δ: 1.051 (d, J=7 Hz, 6H); 2.025-2.400 (m, 3H); 2.852 (brs, 2H); 2.916 (s, 3H); 3.026 (d, J=7 Hz, 2H); 3.15-3.38 (m, 4H); 3.533 (t, J=6 Hz, 2H); 3.917 (brs, 2H); 5.995 (brs, 1H); 6.257 (s, 4H); 6.777,7.318 (ABq, J=9 Hz, 4H)

EXAMPLE 99 4-(4-Methoxyphenyl)-1-{3-(4-morpholinyl)propyl}-1,2,5,6-tetrahydropyridine (I a-99) ##STR71##

A stirred mixture of 1.147 g of the compound (IV-8) and 1.76 ml of morpholine is refluxed for 1 hour. After removal of the reagent, the residue is purified by silica gel column chromatography (CH₂ Cl₂ /MeOH/NH₄ OH=64/8/1-32/6/1) to prepare 1.34 g of the compound (III-59) as oily substance. The oily product is dissolved in 10 ml of CF₃ COOH and refluxed for 1 hour. After removal of the reagent, the residue is poured into aq. NH₄ OH and extracted with methylene chloride. The organic layer is dried and evaporated under reduced pressure to prepare 1.012 g of the oily product. The oily product is subjected to column chromatography with silica gel; eluting with CH₂ Cl₂ /MeOH(19/1). The eluate is recrystallized from Et₂ O-n-hexane to prepare of 637 mg (Yield: 50.2%) of the compound (I a-99) as colorless needles. mp. 69.0°-70.5° C.

Anal Calcd. (%) for C₁₉ H₂₈ N₂ O₂ : C, 72.12; H, 8.92; N, 8.85. Found: C, 72.01; H, 8.88; N, 9.05.

IR (CHCl₃) : 2490, 1610, 1572, 1512, 1466, 1446, 1417, 1402, 1378

NMR (CHCl₃) δ: 1.799 (quint, J=7 Hz, 2H); 2.33-2.63 (m, 10H); 2.7 06 (t, J=5 Hz, 2H); 3.151 (q, J=4 Hz, 2H); 3.725 (t, J=5 Hz, 4H); 3.802 (s, 3H); 5.969 (quint, J=2 Hz, 1H); 6.851, 7.322 (ABq, J=9 Hz, 4H)

Example 100

4-(4-tert-Butylphenyl)-1-{3-(2,6-dimethylmorpholino)propyl}-1,2,5,6-tetrahydropyridine (I a-100) ##STR72##

(1) A mixture of 1.150 g of the compound (IV-2) and 2.29 ml of cis 2,6-dimethylmorpholine is stirred at 103°-135° C. for 4 hours. After removal of the reagent, the residue is poured into aq.NaOH and extracted with methylene chloride. The organic layer is dried and evaporated under reduced pressure. The residue is purified by column chromatography with silica gel, eluting with CH₂ Cl₂ -MeOH (15/1-5/1) to prepare 1.37 g (Yield: 95.0%) of the compound (III-60) as crystals. mp. 137.5°-138.0° C. (dec.)

IR (CHCl₃): 3610, 3010, 2970, 2870, 2820, 1780, 1605, 1512 cm⁻¹

NMR (CDCl₃) δ: 1.161 (d, J=6 Hz, 6H); 1.319 (s, 9H); 1.63-1.88 (m, 7H); 2.215 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.30-2.60 (m, 6H); 2.753 (dd, J₁ =12 Hz, J₂ =2 Hz, 2H); 2.875 (dd, J₁ =11 Hz, J₂ =2 Hz, 2H); 3.60-3.75 (m, 2H); 7.377,7.451 (ABq, J=9 Hz, 4H)

(2) A solution of 1.35 g of the compound (III-60) in 10 ml of CF₃ COOH is refluxed for 4 hour. After removal of the reagent, the residue is poured into aq.NaHCO₃ and extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated under reduced pressure. The oily residue is purified by column chromatography with silica gel, eluting with CH₂ Cl₂ /MeOH (25/1-15/1) to prepare. 1.29 g (Yield: 86.8%) of the compound (I a-100) as an oil. The maleate is recrystallized from MeOH-iPrOH to prepare colorless needles. mp. 192.0°-193.0° C.

Anal Calcd. (%) for C₂₄ H₃₈ N₂ O. 2C₄ H₄ O₄ : C, 63.58; H, 7.79; N, 4.64. Found: C, 63.77; H, 7.69; N, 4.65.

IR (Nujol): 1707, 1618 cm⁻¹

NMR (CDCl₃): 1.260 (d, J=7 Hz, 6H); 1.330 (s, 9H); 2.20-2.40 (m, 2H); 2.491 (t, J=12 Hz, 2H); 2.80-2.95 (m, 2H); 3.111 (t, J=8 Hz, 2H); 3.28-3.40 (m, 4H); 3.542 (t, J=6 Hz, 2H); 3.80-4.00 (m, 4H); 3.542 (t, J=6 Hz, 2H); 3.80-4.00 (m, 4H); 6.02-6.08 (m, 1H); 6.283 (s, 2H); 7.355,7.422 (ABq, J=9 Hz, 4H)

EXAMPLE 101-104

The reaction is performed in the same manner as Example 100 to prepare the compound (I a). The reaction conditions are shown in Tables 13 and 14.

                                      TABLE 13                                     __________________________________________________________________________      ##STR73##                                                                     Ex.                   reaction                                                                             purification                                                                             product                                  No.                                                                               (IV) (X I)     solvent                                                                            condition                                                                            condition g (Yield)                                                                           m.p. (°C.)                                                                    IR                            __________________________________________________________________________     101                                                                               X = Me                                                                              Z = O, R = H                                                                             --  2 hr. CH.sub.2 Cl.sub.2 /MeOH =                                                                III-61                                                                              103.0-                                                                               (CHCl.sub.3)                     3.55 g                                                                              5.77 g        reflux                                                                               15/1-5/1  4.23 g                                                                              104.5 3600, 3020, 2950, 2920,                                                        2820,                                                               (96.0%)    1513, 1472                    102                                                                               X = Cl                                                                              Z = O, R = H                                                                             --  130-135° C.                                                                   --        III-62                                                                              236.0-                                                                               (Nujol)                          5.1 g                                                                               7.71 g        2.5 hr.         5.97 g                                                                              237.0 3440, 2930, 2870, 2640,                                                        2550,                                                               (99.5%)    2460                          103                                                                               X = t-Bu                                                                            Z = NH, R = Me                                                                           DMF 95-100° C.                                                                    CH.sub.2 Cl.sub.2 /MeOH/                                                                 III-63                                                                              --    (CHCl.sub.3)                     2.35 g                                                                              1.73 g    20 ml                                                                              2 hr. NH.sub.4 OH =                                                                            1.92 g     3000, 3330, 2960, 2820,                                                        2470,                                                     30/6/1    (65.3%)    1665, 1635, 1605, 1590,                                                        1510                          104                                                                               X = Cl                                                                              Z = NH, R = Me                                                                           DMF 80-85° C.                                                                     CH.sub.2 Cl.sub.2 /MeOH/                                                                 III-64                                                                              --    (CHCl.sub.3)                     2.05 g                                                                              1.62 g    15 ml                                                                              3.5 hr.                                                                              NH.sub.4 OH =                                                                            2.10 g     3590, 3160, 2930, 2810,                                                        2490,                                                     32/6/1    (80.9%)    1677, 1596,                   __________________________________________________________________________                                                      1492                     

                                      TABLE 14                                     __________________________________________________________________________     Ex.            reaction                                                                              purification   product                                   No. (III)                                                                              CF.sub.3 COOH                                                                         condition                                                                             condition      g (Yield)                                                                           m.p. (°C.)                                                                     IR                            __________________________________________________________________________     101 (III-61)                                                                           45 ml  2.5 hr.                                                                               CH.sub.2 Cl.sub.2 /MeOH = 15/1-5/1                                                            Ia-101                                                                              186.5- (Nujol)                           4.45 g     reflux                3.99 g                                                                              188.5*.sup.1                                                                          1709, 1621                                                         (92.0%)                                   102 (III-62)                                                                           45 ml  7 hr.  CH.sub.2 Cl.sub.2 /MeOH = 15/1-5/11                                                           Ia-102                                                                              185.5- (Nujol)                           3.78 g     reflux                3.00 g                                                                              186.5*.sup.1                                                                          2300(br), 1709, 1622                                               (84.2%)                                   103 (III-63)                                                                           20 ml  room   CH.sub.2 Cl.sub.2 /MeOH/                                                                      Ia-103                                                                              235.0- (Nujol)                           1.92 g     temperature                                                                           NH.sub.4 OH = 128/16/1                                                                        1.60 g                                                                              250.0*.sup.2                                                                          3440, 3410, 2670, 2580,                                                        2470                                         2.5 hr. reflux        (87.4%)     2420, 1658, 1555, 1507        104 (III-64)                                                                           25 ml  room   CH.sub.2 Cl.sub.2 /MeOH/                                                                      Ia-104                                                                              179.0- (Nujol)                           2.10 g     temperature                                                                           NH.sub.4 OH = 128/16/1                                                                        1.79 g                                                                              181.0*.sup.2                                                                          3600, 2680, 2530, 2440,                                                        1642                                         15 hr. reflux         (89.6%)     1597, 1496                    __________________________________________________________________________      *.sup.1 maleate                                                                *.sup.2 hydrochloride                                                    

EXAMPLE 105 1-[3-{4-(3,4-Dimethoxyphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propylcarbamoyl]-2-oxopyrrolidine (I a-105) ##STR74##

To a solution of 3.76 g of 4-(3,4-dimethoxyphenyl)-1,2,5,6-tetrahydropyridine (V-7), which was prepared by the reaction of 4-hydroxy-4-(3,4-dimethoxyphenyl)piperidine and p-toluenesulfonic acid, and 2.94 g of 1-(3-chloropropylcarbamoyl)-2-oxopyrrolidine in 35 ml of DMF is added 3.98 g of K₂ CO₃ and 3.22 g of NaI. The reaction mixture is stirred at 100°-105° C. for 6 days under nitrogen gas. After cooling to room temperaure, the mixture is diluted with ethyl acetate, washed with brine and dried over MgSO₄. After removal of the solvent, the residue is subjected to column chromatography with silica gel, eluting with CH₂ Cl₂ /MeOH (20/1) to prepare 1.78 g (Yield: 33.4%) of the compound (I a-105) as solid. The oxalate is recrystallized from iPrOH-MeOH to prepare needles. mp. 178.0°-182.0° C.

Anal Calcd. (%) for C₂₃ H₃₁ N₃ O₈.1/5 H₂ O: C, 57.35; H, 6.33; N, 8.67. Found: C, 57.42; H, 6.58; N, 8.73.

IR (Nujol): 3310, 1725(sh), 1708, 1682, 1675, 1600, 1580, 1545, 1545, 1520

NMR (CDCl₃): 1.764 (quint, J=7 Hz, 2H); 1.954 (quint, J=8 Hz, 2H); 2.44-2.51 (m, 4H); 2.530 (t, J=8 Hz, 2H); 2.646 (t, J=5 Hz, 2H); 3.094 (q, J=3 Hz, 2H); 3.328 (q, J=7 Hz, 2H); 3.795 (t, J=7 Hz, 2H); 3.809, 3.827 (sx2, 6H); 5.915 (quint, J=3 Hz, 1H); 6.755 (d, J=9 Hz, 2H); 6.84-6.89 (m, 2H); 8.434 (brs, 1H)

EXAMPLE 106

1-[3-{4-(4-Methoxyphenyl)-1,2,5,6-tetrahydropyridin-1-yl}-propylcarbamoyl]-2-oxopyrrolidine (I a-106) ##STR75##

The compound (V-8) is reacted in the same manner as Example 105 to prepare the compound (I a-106). mp. 199.5°-200.0° C. (dec.)

Anal Calcd. (%) for C₂₂ H₂₉ N₃ O₇ : C, 58.81; H, 6.31; N, 9.32. Found: C, 59.02; H, 6.53; N, 9.39.

IR (Nujol): 3300, 2730, 2620, 1700, 1685, 1612, 1548, 1529, 1465

NMR (CDCl₃): 1.90-2.10 (m, 4H); 2.590 (t, J=7 Hz, 2H); 2.80-2.86 (m, 2H); 3.23-3.30 (m, 2H); 3.33-3.52 (m, 4H); 3.778 (s, 3H); 3.898 (m, 2H); 5.995 (s, 1H); 6.893, 7.379 (ABq, J=8 Hz, 4H)

EXAMPLE 107 1-[{-(4-Tolyl)-1,2,5,6-tetrahydropyridin-1-yl}butylcarbamoyl]-2-oxopyrrolidine (I a-107) ##STR76##

(1) To a solution of 4.00 g of the compound (II-8) and 4.675 g of N-Boc-β-alanine in 90 ml of THF are added 5.178 g of 1,3-dicyclohexylcarbodiimide and 848 mg of 1-hydroxybenzotriazole hydrate. The reaction mixture is stirred at room temperature for 2 hours and 10 minutes. After removal of precipitates, the reaction mixture is concentrated under reduced pressure. The residue is poured into d.HCl and extracted with CH₂ Cl₂. The organic layer is washed with aq.NaHCO₃ and water in order, dried over MgSO₄ and evaporated under reduced pressure. The residue is subjected to column chromatography with silica gel, eluting with toluene/acetone (3/1-2/1) to prepare 6.862 g of crystalline residue. It is recrystallized from methylene chloride-ether-n-hexane to prepare 6.674 g (Yield: 84.8%) of the compound (IV-9) as colorless needles. mp. 161.5°-163.0° C.

Anal calcd. (%) for C₂₁ H₃₂ N₂ O₄ : C, 67.18; H, 8.46; N, 7.50. Found: C, 66.99; H, 8.57; N, 7.44.

IR (CHCl₃): 3597, 3457, 1709, 1628, 1508, 1474, 1448, 1393, 1369

NMR (CDCl₃) δ: 1.432 (s, 9H); 1.75,2.05 (m, 8H); 2.344 (s, 3H); 2.147 (t, J=7 Hz. 2H); 3.04,3.20 (m, 3H); 3.560 (td, J₁ =12 Hz, J₂ =4 Hz, 1H); 3.737 (d, J=14 Hz, 1H); 4.548 (d, J=13 Hz, 1H); 4.833 (brs, 1H); 7.177,7.353 (ABq, J=8 Hz, 4H)

(2) A solution of 6.654 g of the compound (IV-9) in 13 ml of CF₃ COOH is stirred at room temperature for 2.5 hours. After removal of the excess reagent, 6.36 g of the crystalline residue is obtained. The residue is recrystallized from MeOH-Et₂ O to prepare 5.798 g of colorless plates. Then to a solution of 4.818 g of the plates in 30 ml of methanol is added 5 ml of triethylamine. After removal of the solvent to dryness, the resulting solid is dropwise added to a stirred suspension of 737 mg of LiAlH₄ in 80 ml of THF at room temperature and stirred at the same temperature for 2.5 hours. After decomposition of the excess reagent by careful addition of water, the resulting precipitate is filtered off. The organic layer is evaporated to dryness to prepare 3.612 g of the yellow oily residue. The residue is subjected to column chromatography with silica gel, eluting with CHCl₃ /MeOH/c.NH₄ OH (32/4/0.5-32/6/1) to prepare 1.341 g (Yield: 42.4%) of the compound (V-9).

(3) A mixture of 1.341 g of the compound (V-9) and 1.126 g of 1-phenoxycarbonyl-2-oxopyrrolidine is heated at 115° C. for 1 hour 43 minutes. The reaction mixture is purified by column chromatography with silica gel, eluting with toluene/acetone (2/1- 1/l) followed by recrystallization from Et₂ O-n-hexane to prepare 540 mg (Yield: 24.7%) of the compound (I a-107) as prisms. mp. 104.0°-104.5° C.

Anal Calcd. (%) for C₂₁ H₂₉ N₃ O₂ : C, 71.05; H, 8.22; N, 11.84. Found: C, 70.95; H, 8.22; N, 11.82.

IR (CHCl₃): 3325, 1714, 1682, 1602, 1548, 1516, 1490, 1461, 1442, 1387

NMR (CDCl₃) δ: 1.62,1.66 (m, 4H); 2.025 (quint, J=7 Hz, 2H); 2.330 (s, 3H); 2.30-2.73 (m, 8H); 3.145 (q, J=3 Hz, 2H); 3.338 (q, J=6 Hz, 2H); 3.858 (t, J=7 Hz, 2H); 6.016 (quint, J=2 Hz, 1H); 7.11 7, 7.283 (ABq, J=8 Hz, 4H); 8.430 (brs, 1H)

EXAMPLE 108 1-[{5-(4-Tolyl)-1,2,5,6-tetrahydropyridin-1-yl}pentylcarbamoyl]-2-oxopyrroridine (I a-108) ##STR77##

A mixture of 4.675 g of BocNH(CH₂)₄ COOH and 4.00 g of the compound (II-8) is treated in the same manner as Example 107 (1)-(3) to prepare 392 mg (Yield: 15.0%) of the compound (I a-108). mp. 58.5°-59.5° C.

Anal Calcd. (%) for C₂₂ H₃₁ N₃ O₂ : C, 71.23; H, 8.42; N, 11.46. Found: C, 71.51; H, 8.46; N, 11.37.

IR (CHCl₃): 3321, 1714, 1681, 1548, 1516, 1489, 1461, 1387

NMR (CDCl₃ --CD₃ OD) δ: 1.32-1.45 (m, 2H); 1.52-1.70 (m, 4H); 2.039 (quint, J=7 Hz, 2H); 2.333 (s, 3H); 2.429-2.507 (m, 2H); 2.615 (t, J=8 Hz, 4H); 2.723 (t, J=6 Hz, 2H); 3.161 (q, J=3 Hz, 2H); 3.303 (q, J=6 Hz, 2H); 3.854 (t, J=7 Hz, 2H); 6.032 (s, 1H); 7.126, 7.292 (ABq, J=8 Hz, 4H); 8.460 (brs, 1H)

EXAMPLE 109 1-{3-(3,4-Dichlorophenoxy)propyl}-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine (I a-109) ##STR78##

(1) A mixture of 3.6 g of 3-(3,4-dichlorophenoxy)propylchloride, which was prepared by the reaction of 3,4-dichlorophenol with 3-bromopropylchloride, and 3.12 g of 4-hydroxy-4-(4-methoxyphenyl)piperidine, 4.15 g of K₂ CO₃, and 3.37 g of NaI in 35 ml of DMF is stirred at 105° C. for 10 hour. The reaction mixture is poured into ice-water, and the resulting precipitates are extracted with methylene chloride. The organic layer is dried and evaporated under reduced pressure. The residue is purified by column chromatography with silica gel, eluting with CH₂ Cl₂ /MeOH (20/1-10/1) followed by recrystallization from methylene chloride to prepare 5.86 g (Yield: 95.2%) of the compound (III-65) as colorless needles. mp. 131.0°-132.0° C.

Anal Calcd. (%) for C₂₁ H₂₅ N₂ O₃ Cl₂ : C, 61.39; H, 6.20; N, 3.55; Cl, 17.28. Found: C, 61.47; H, 6.14; N, 3.41; Cl, 17.30.

IR (CHCl₃): 3600, 1612, 1595, 1568, 1513, 1480(sh), 1468

NMR (CDCl₃) δ: 1.563 (s, 1H); 1.772 (dd, J₁ =14 Hz, J₂ =3 Hz, 2H); 1.999 (quint, J=6 Hz, 2H); 2.137 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.478 (td, J₁ =12 Hz, J₂ =2 Hz, 2H); 2.575 (t, J=7 Hz, 2H); 2.811 (J₁ =11 Hz, J₂ =3 Hz, 2H); 3.803 (s, 3H); 4.004 (t, J=6 Hz, 2H); 6.760 (dd, J₁ =9 Hz, J₂ =3 Hz, 1H); 6.887 (d, J=9 Hz, 2H); 7.013 (d, J=3 Hz, 1H); 7.308 (d, J=9 Hz, 1H); 7.438 (d, J=9 Hz, 2H)

(2) To a stirred solution of 2.08 g of the compound (III-65) in 50 ml of methylene chloride is added 1.44 ml of BBr₃ under ice-cooling. After removal of the reagent, the residue is poured into aq.NaHCO₃ and extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated under reduced pressure. The resulting oily residue 1.91 g is dissolved in 20 ml of CF₃ COOH and refluxed for 2 hour. After removal of the reagent, the residue is poured into aq.NaHCO₃ and extracted with ethylacetate. The organic layer is washed, dried and evaporated. The residue is purified by column chromatography with silica gel, (toluene/ethyl acetate(1/1)--CH₂ Cl₂ /MeOH (20/1)) to prepare 270 mg (Yield: 33%) of the compound (I a-109) as a solid. The maleate is recrystallized from MeOH-iPrOH to prepare needles. mp. 167.0°-168.0° C. (dec.)

Anal Calcd. (%) for C₂₀ H₂₁ NO₂ Cl₂ : C,58.08; H,5.05; N,2.93; Cl,14.55. Found: C,58.31; H,5.10; N,2.83; Cl,14.34.

EXAMPLE 110 1-{3-(3,4-Dichlorophenoxy)propyl}4-(3,4-dichlorophenyl)-1,2,5,6-tetrahydropyridine (I a-110) ##STR79##

(1) 3-(3,4-dichlorophenoxy)propylchloride 1.38 g and 4-hydroxy-4-(3,4-dichlorophenyl)piperidine 1.35 g are reacted in the same manner as Example 109 (1) to prepare 2.40 g (Yield: 97.5%) of 1-{3-(3,4-dichlorophenoxy)propyl}-4-hydroxy-4-(3,4-dichlorophenyl) piperidine (III-66). mp. 118.0°-118.5° C.

(2) A solution of 1.61 g of the compound (III-66) in 20 ml of trifluoroacetic acid is refluxed for 3.5 hours. After removal of the reagent, the residue is poured into aq.NaHCO₃ and extracted with methylene chloride. The organic layer is washed, dried and evaporated. The residue is purified by column chromatography with silica gel; eluting with CH₂ Cl₂ /MeOH(25/1) to prepare 1.45 g (Yield 94.0%) of the compound (I a-110) as oxalate. The oxalate is recrystallized from MeOH-iPrOH to prepare the compound (I a-110) as needles. mp. 163.5°-165.0° C. (dec.)

Anal Calcd. (%) for C₂₀ H₁₉ NO₂ Cl₄ : C, 50.43; H, 4.09; N, 2.72; Cl, 27.15. Found: C, 50.70; H, 4.06; N, 2.69; Cl, 27.21.

IR (Nujol): 2930, 1713, 1695(sh), 1615, 1597, 1563

NMR (CDCl₃): 2.045 (quint, J=7 Hz, 2H); 2.657 (t, J=8 Hz, 2H); 2.554 (m, 2H); 2.745 (t, J=5 Hz, 2H); 3.202 (q, J=3 Hz, 2H); 4.026 (t, J=6 Hz, 2H); 6.110 (m, 1H); 6.766 (dd, J₁ =19 Hz, J₂ =3 Hz, 1H); 7.0 15 (d, J=3 Hz, 1H); 7.19-7.47 (m, 4H)

EXAMPLE 111 1-{3-(3,4-Dichlorophenoxy)propyl}-4-(4-trifluoromethylphenyl)-1,2,5,6-tetrahydropyridine (I a-111) ##STR80##

(1) 3-(3,4-dichlorophenoxy)propylchloride 2.00 g and 4-hydroxy-4-(4-trifluoromethylphenyl)piperidine 1.95 g are reacted in the same manner as Example 109 (1) to prepare 3.16 g (Yield: 88.7%) of the compound (III-67). mp. 196.0°-196.5° C.

(2) A solution of 2.65 g of the compound (III-67) in 30 ml of trifluoroacetic acid is refluxed for 41 hours. After removal of the reagent, the residue is poured into aq.NaHCO₃ and extracted with ethyl acetate. The organic layer is dried and evaporated. The residue is purified by column chromatography with silica gel. (toluene/ethyl acetate (3/1), CH₂ Cl₂ /MeOH(25/1)) to prepare 1.65 g (Yield: 65.9%) of the compound (I a-111) as a solid, which is recrystallized from Et₂ O to prepare colorless needles, mp. 83.5°-84.0° C. The oxalate melts at mp. 195.5°-196.0° C.

Anal Calcd. (%) for C₂₁ H₂₀ NO₂ Cl₂ F₃.C₂ H₂ O₄ : C, 52.93; H, 4.33; N, 2.71; Cl, 13.42; F, 11.08. Found: C, 53.09; H, 4.26; N, 2.69; Cl, 13.65; F, 10.95.

IR (CHCl₃): 2950, 2930, 2830, 2790, 1618, 1597, 1469

NMR (CDCl₃): 2.052 (quint, J=7 Hz, 2H); 2.52-2.65 (m, 2H); 2.661 (t, J=7 Hz, 2H); 2.759 (t,J=6 Hz, 2H); 3.222 (q, J=3 Hz, 2H); 6.171 (m, 1H); 6.765 (dd, J₁ =9 Hz, J₂ =3 Hz, 1H); 7.015 (d, J=3 Hz, 1H); 7.312 (d, J=9 Hz, 1H); 7.479, 7.574 (ABq, J=8 Hz, 4H)

REFERENCE EXAMPLE 1 4-Hydroxy-4-(3,4-dichlorophenyl)piperidine (II-1) ##STR81##

A mixture of 64.2 g of 1-ethoxycarbonyl-4-hydroxy-4-(3,4-dichlorophenyl)piperidine (X-1) and a solution of 72.4 g of KOH in 700 ml of nBuOH is refluxed for 2 hours and evaporated. The reaction mixture is concentrated under reduced pressure and extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated. The resulting crystalline residue is recrystallized from ethyl acetate to prepare 44.7 g (Yield: 90.0%) of the compound (II-1). mp. 144.5°-146.0° C.

Anal Calcd. (%) for C₁₄ H₁₇ NO₃ Cl₂ : C, 53.62; H, 5.26; N, 5.68; Cl, 28.98. Found: C, 53.68; H, 5.32; N, 5.69; Cl, 28.81.

IR (Nujol): 3320, 3100, 1438

NMR (CD₃ OD) δ: 1.651 (dd, J₁ =12 Hz, J₂ =2 Hz, 2H); 1.936 (td, J₁ =12 Hz, J₂ =5 Hz, 2H); 1.651 (dd, J₁ =12 Hz, J₂ =2 Hz, 2H); 3.074 (td, J₁ =12 Hz, J₂ =3 Hz, 2H); 7.402 (dd, J₁ =8 Hz, J₂ =2 Hz, 1H); 7.480 (d, J=8 Hz, 1H); 7.662 (d, J=2 Hz, 1H)

REFERENCE EXAMPLE 2-19

The reaction is performed in the same manner as Reference Example 1 to prepare the compound (II). The reaction conditions and physical constants are shown in Tables 15 and 16.

                                      TABLE 15                                     __________________________________________________________________________      ##STR82##                                                                     Ref. (X)              reflux                                                                              (II) g (Yield)                                      Ex. No.                                                                             X =  Base solvent                                                                               time m.p. (°C.)                                                                      IR                                          __________________________________________________________________________     2    CF.sub.3 (p)                                                                        KOH  EtOH   5 hours                                                                             (II-2)                                                   27.3 g                                                                              (28.07 g)                                                                           (450 ml)    13.24 g (63.0%)                                          (X-2)                                                                     3    n-Pr (p)                                                                            KOH  n-BuOH 5.5 hours                                                                           (II-3)                                                   44.0 g                                                                              (49.3 g)                                                                            (640 ml)    30.47 g (92.0%)                                          (X-3)                                                                     4    Et (p)                                                                              KOH  n-BuOH 2 days                                                                              (II-4)                                                   22.42 g                                                                             (26.37 g)                                                                           (500 ml)    13.88 g (83.7%)                                          (X-4)                                                                     5    Ph (p)                                                                              KOH  n-BuOH 15 hours                                                                            (II-5)                                                   18.65 g                                                                             (18.70 g)                                                                           (500 ml)    13.44 g (92.6%)                                          (X-5)                                                                     6    t-Bu (p)                                                                            KOH  n-BuOH 5.5 hours                                                                           (II-6)                                                   46.67 g                                                                             (50.9 g)                                                                            (700 ml)    33.64 g (92.0%)                                          (X-6)                                                                     7    CH.sub.3 (p)                                                                        KOH  BuOH   3.5 hours                                                                           (II-8)  (Nujol)                                          49.86 g                                                                             (61.8 g)                                                                            (700 ml)    33.20 g (92.0%)                                                                        3310, 1598, 1502, 1490                           (X-7)                 135.5-137.5                                                                            1445                                        8    CH.sub.3 (m)                                                                        KOH  EtOH   6 days                                                                              (II-9)  (Nujol)                                          21.2 g                                                                              (26.3 g)                                                                            (450 ml)    10.25 g (66.6%)                                                                        3440, 3280, 3220, 3179                           (X-8)                 154.5-155.5                                                                            1606, 1590, 1490, 1475                      9    CH.sub.3 (o)                                                                        KOH  EtOH   5 days                                                                              (II-10) (Nujol)                                          14.7 g                                                                              (18.21 g)                                                                           (350 ml)    7.90 g (74.0%)                                                                         3440, 3280, 3220, 3170                           (X-89                 141.0-142.0                                                                            1608, 1590, 1490                            10   3,4-diMe                                                                            KOH  EtOH   10 days                                                                             (II-11) (Nujol)                                          20.2 g                                                                              (23.76 g)                                                                           (500 ml)    13.97 g (93.5%)                                                                        3590, 3380, 1600, 1502                           (X-10)                --      1467, 1448                                  11   3,4-diMe                                                                            KOH  EtOH   12 days                                                                             (II-12) (Nujol)                                          22.7 g                                                                              (26.7 g)                                                                            (650 ml)    14.85 g (88.4%)                                                                        3280, 3120(br), 1605                             (X-11)                182.0-183.0                                                                            1415                                        12   Cl (m)                                                                              KOH  EtOH   2 days                                                                              (II-13) (Nujol)                                          22.2 g                                                                              (25.5 g)                                                                            (350 ml)    13.68 g (82.6%)                                                                        3220, 3080, 1595, 1570                           (X-12)                100.0-101.0                                                                            1432, 1408                                  13   Cl (o)                                                                              NaOH THF/H.sub.2 O                                                                         5 days                                                                              (II-14) (KBr)                                            9.2 g                                                                               (3.89 g)                                                                            (10 ml/20 ml)                                                                              4.95 g (72.0%)                                                                         3440, 3280, 3060, 1475                           (X-13)                166.5-167.5                                                                            1442, 1430                                  14   3,5-diCl                                                                            KOH  EtOH   11 days                                                                             (II-15) (Nujol)                                          25.11 g                                                                             (25.74 g)                                                                           (550 ml)    15.5 g (79.8%)                                                                         3310, 3100, 3080, 1591                           (X-14)                213.0-214.0                                                                            1568, 1450, 1425, 1410                      15   Br (p)                                                                              KOH  EtOH   10 days                                                                             (II-16) (Nujol)                                          21.0 g                                                                              (20.87 g)                                                                           (500 ml)    9.23 g (56.3%)                                                                         3280, 3050, 1588, 1492                           (X-15)                159.5-161.5                                                                            1478, 1420                                  16   F (p)                                                                               KOH  Dioxane/H.sub.2 O                                                                     6 days                                                                              (II-17) (Nujol)                                          23.2 g                                                                              (17.36 g)                                                                           (170/70 ml) 9.82 g (58.8%)                                                                         3280, 3130, 1602, 1512                           (X-16)                --      1455                                        17   CF.sub.3 (m)                                                                        KOH  nBuOH  2 hours                                                                             (II-18) (CHCl.sub.3)                                     Cl (p)                                                                              (42.7 g)                                                                            (580 ml)    22.30 g (67.0%)                                                                        3595, 2950, 2850, 1607                           41.8 g                135.0-136.5                                                                            1576, 1483                                       (X-17)                                                                    18   .sup.*1                                                                             KOH  EtOH   2 days                                                                              (II-19) (Nujol)                                          (X-18)                                                                              (18.30 g)                                                                           (350 ml)    11.88 g 3290, 1540, 1417                                 27.1 g                149.5-150.0                                         19   .sup.*2                                                                             KOH  nBuOH  2 days                                                                              (II-20) (Nujol)                                          (X-19)                                                                              (19.82 g)                                                                           (500 ml)    9.51 g (62.1%)                                                                         3280, 1640, 1540                                 19.7 g                151.0-152.5                                         __________________________________________________________________________      ##STR83##                                                                      ##STR84##                                                                

                                      TABLE 16                                     __________________________________________________________________________     Compd.                                                                              m.p. (°C.)                                                                      Anal Calcd. (%)                                                   No.  (solvent*)                                                                             Found(%)  IR (cm.sup.-1)                                                                         NMR (δ)                                   __________________________________________________________________________     II-2 136.0-137.0                                                                            C.sub.12 H.sub.14 NOF.sub.3 :                                                            (Nujol) (CD.sub.3 OD)                                        (ethyl acetate)                                                                        C, 58.83 (58.77)                                                                         3290, 1619, 1443                                                                       1.680(d-d, J.sub.1 =14Hz, J.sub.2 =2Hz,                                        2H); 2.004(t-d, J.sub.1 =14Hz, J.sub.2                                         =5Hz, 2H);                                                   H, 5.74 (5.75)                                                                           1439, 1422, 1410                                                                       2.866 (d-d, J.sub.1 =13Hz, J.sub.2 =2Hz,                                       2H); 3.107(t-d, J.sub.1 =13Hz, J.sub.2                                         =2Hz,                                                        N, 5.73 (5.71)    2H); 7.625(d, J=9Hz, 2H); 7.698(d, J=9Hz,                                      2H)                                                          F, 23.13 (23.24)                                                  II-3 178.5-179.5                                                                            C.sub.14 H.sub.21 NO.C.sub.2 H.sub.2 O.sub.4                                             (CHCl.sub.3)                                                                           (CDCl.sub.3)                                         (oxalate)                                                                              C, 61.77 (62.12)                                                                         3600, 3350(br).                                                                        0.933(t, J=7Hz, 3H); 1.620(sextet, J=8Hz,                                      2H); 1.876(d, J=14Hz,                                (i-PrOH)                                                                               H, 7.42 (7.49)                                                                           1593, 1510, 1468                                                                       2H); 2.330(t-d, J.sub.1 =14Hz, J.sub.2                                         =4Hz, 2H); 2.564(t, J=8Hz, 2H); 3.244                        N, 4.50 (4.53)                                                                           1422    (d, J =12Hz, 2H); 3.367(t, J=12Hz, 2H);                                        7.164(d, J=*hz, 2H); 7.40                                                      (d, J=8Hz, 2H)                                  II-4 119.0-120.0                                                                            C.sub.13 H.sub.19 NO                                                                     (CHCl.sub.3)                                                                           (CD.sub.3 OD)                                        (Et.sub.2 O--)                                                                         C, 75.97 (76.05)                                                                         3600, 1510, 1469                                                                       1.204(t, J=8Hz, 3H); 1.676(d-d, J.sub.1                                        =14Hz, J.sub.2 =2Hz, 2H); 1.933                      ethyl acetate)                                                                         H, 9.33 (9.33)                                                                           1440, 1420, 1410                                                                       (t-d, J.sub.1 =14Hz, J.sub.2 =5Hz, 2H);                                        1.616(q, J=8Hz, 2H); 2.852(d-d, J.sub.1                                        =12                                                          N, 6.78 (6.82)                                                                           (sh)    Hz, J.sub.2 =3Hz, 2H); 3.084(t-d, J.sub.1                                      =12Hz, J.sub.2 =3Hz, 2H); 7.156(d, J=8                                         Hz, 2H); 7.397(d, J=8Hz, 2H)                    II-5 182.5-184.0                                                                            C.sub.17 H.sub.19 NO.1/6H.sub.2 O                                                        (Nujol) (CDCl.sub.3 -CD.sub.3 OD=4/1)                        (MeOH-- C, 79.84 (79.65)                                                                         3320, 1595, 1581                                                                       1.804(d, J=12Hz, 2H); 2.052(t-d, J.sub.1                                       =14Hz, J.sub.2 =5Hz, 2H); 2.096(d-d,                 CH.sub.2 Cl.sub.2)                                                                     H, 7.48 (7.60)                                                                           1563, 1490, 1450                                                                       J.sub.1 =13Hz, J.sub.2 =2Hz, 2H);                                              3.172(t-d, J.sub.2 =12Hz, J.sub. 2 =3Hz,                                       2H); 7.29-                                                   N, 5.44 (5.46)    7.63(m, 9H)                                     II-6 185.0-186.0                                                                            C.sub.15 H.sub.23 NO.H.sub.2 O                                                           (Nujol) (CD.sub.3 OD)                                        (CHCl.sub.3 --                                                                         C, 71.18 (71.67)                                                                         3480(sh), 3390,                                                                        1.301(s, 9H); 1.684(d-d, J.sub.2 =14Hz,                                        J.sub.2 =2Hz, 2H); 1.839(t-d, J.sub.1 =14            MeOH)   H, 9.86 (10.02)                                                                          3320, 3290, 3090                                                                       Hz, J.sub.2 =4Hz, 2H); 2.857(d-m, J.sub.1                                      =12Hz, 2H); 3.086(t-d, J.sub.1 =13Hz,                        N, 5.67 (5.57)                                                                           1668, 1508, 1470                                                                       J.sub.2 =3Hz, 2H); 7.360(d, J=9Hz, 2H);                                        7.404(d, J=9Hz)                                 __________________________________________________________________________

EVALUATION OF BIOLOGICAL ACTIVITY Experiment

After the decapitation of rats, the objective tissues were rapidly removed and each was weighed. Each tissue was homogenized with twenty-fold amount of ice-cold 50 mM Tris-HCl buffer (pH7.8), homogenized, and centrifuged at 40,000×g for 10 minutes. The supernatant was removed and pellets were then resuspended in the buffer and recentrifuged. The procedure is repeated 3 times. Then these obtained samples were freeze-dried in liquid nitrogen and preserved at -80° C. On the test day, the sample was thawed at room temperature and centrifuged at 40,000×g for 10 minutes, the pellets were then suspended in an incubation buffer and used as the receptor preparation. The preparation was added to the mixture containing the labelled ligand and the test drug, and filtered through Whatman GF/C filters and washed to terminate the reaction. Radioactivity on the filters was determined by a liquid scintillation counter and Ki value was calculated.

1. σ receptor

Sigma receptor binding was initiated by the addition of the receptor preparation (cortex tissue, 0.7 mg protein/ml) to a mixture containing 5 nM of [³ H]3PPP [3-hydroxyphenyl-N-(1-propyl)piperidine] and the test compound dissolved in 50 mM Tris-HCl buffer (pH 7.8). Incubation was carried out at 25° C. for 90 minutes. Specific sigma receptor binding was defined as the difference in amount of [³ H]3PPP bound to the tissue in the presence or the absence of 10 μM haloperidol.

2. DA2 receptor

DA2 receptor binding was initiated by the addition of the receptor preparation (striatal tissue, 0.3 mg protein/ml) to a mixture containing 0.2 nM of [³ H]spiroperidol and the test compound dissolved in 50 mM Tris-HCl buffer containing 100 mM-NaCl and 5 mM-KCl (pH 7.4). Incubation was carried out at 37° C. for 10 minutes. Specific DA2 receptor binding was defined as the difference in amount of [³ H]spiroperidol bound to the tissue in the presence or the absence of 10 μM haloperidol. 3. 5HT2 receptor

5HT2 receptor binding was initiated by the addition of the receptor preparation (cortex tissue, 0.5 mg protein/ml) to a mixture containing 1 nM of [³ H]spiroperidol and the test compound dissolved in 50 mM Tris-HCl buffer (pH 7.4). Incubation was carried out at 37° C. for 15 minutes. Specific 5HT2 receptor binding was defined as the difference in amount of [³ H]spiroperidol bound to the tissue in the presence or the absence of 1 mM serotonin.

4. PCP receptor

PCP receptor binding was initiated by the addition of the receptor preparation (cortex tissue, 0.2 mg protein/ml) to a mixture containing 5 mM of [³ H]TCP and the test compound dissolved in 5 mM Tris-HCl buffer (pH 7.8). Incubation was carried out at 25° C. for 30 minutes. Specific PCP receptor binding was defined as the difference in amount of [³ H]TCP bound to the tissue in the presence or the absence of 10 μM PCP.

The test results are shown in Table 17.

                  TABLE 17                                                         ______________________________________                                         Test     Ki (μM)                                                            compound PCP     σ      DA2  5-HT2                                       ______________________________________                                         Ia-2     31      0.0041       4.7  0.55                                        Ia-3     16      0.0095       4.0  1.70                                        Ia-6     49      0.0027       2.2  2.50                                        Ia-8     >62     0.0013       1.20 2.90                                        Ia-9     33      0.0061       1.60 1.20                                        Ia-11    23      0.0026       4.50 4.40                                        Ia-13    26      0.0022       0.32 0.77                                        Ia-24    32      0.0058       1.10 0.38                                        Ia-30    >63     0.0013       2.00 3.70                                        Ia-35    18      0.0018       4.60 3.20                                        Ia-56    44      0.0065       4.50 8.90                                        Ia-57    44      0.0063       2.40 0.14                                        Ia-94    27      0.0013       1.40 1.90                                        Ia-101   >63      0.00031     1.80 7.70                                        Ia-102   >71      0.00071     3.20 5.70                                        Ia-111   >63     0.0029       0.63 0.39                                        Ia-112   >63     0.0025       >21  2.60                                        ______________________________________                                    

From the above, the compound of the present invention has low affinity to DA2 receptor and high affinity to σ receptor, and has useful activity as psychotropic agents. 

What we claim is:
 1. A compound of the formula: ##STR85## wherein Ar is phenyl or thienyl which may have identically or differently one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, substituted or unsubstituted phenyl, trifluoromethyl and hydroxy;R¹ is hydrogen or lower alkyl; the morpholino group may have identically or differently 1 to 3 substituents selected from the group consisting of lower alkyl, halogen, oxo pyrimidine and phenyl, which phenyl may be substituted by hydroxy, lower alkyl, lower alkoxy or halogen; n is an integer of from 2 to 6; p and q each is an integer of 0 or 1, excluding the case where p is 0 when q is 1;or a pharmaceutically acceptable acid addition salt thereof.
 2. A compound according to claim 1, wherein the substituted phenyl on the phenyl or thienyl for Ar is phenyl substituted by one or more substituents selected from the group consisting of hydroxy, lower alkyl, lower alkoxy and halogen. 